Acute Erythroid Leukemia

MONDO:0017858 Pathograph 24 Show in embeddings browser acute myeloid leukemia

Acute erythroid leukemia (AEL, MONDO:0017858; historically FAB M6) is a rare acute myeloid leukemia subtype defined by a predominant, maturation-arrested erythroid population with marked dyserythropoiesis. Classification has moved substantially and is scoped narrowly here. WHO-HAEM5 (2022) restricts AEL to what was previously called pure erythroid leukemia: erythroid predominance (usually >=80% of bone marrow elements) of which >=30% are proerythroblasts, with a high prevalence of biallelic TP53 alterations; the diagnosis supersedes AML with myelodysplasia-related changes (AML-MR). The ICC (2022) reaches a closely related but not identical position, folding pure erythroid leukemia into the broader "AML with mutated TP53" category rather than keeping a separate erythroid-defined entity. Both classifications retired the older, broader "erythroleukemia" (myeloid/erythroid, FAB M6a) category, which lacked a reproducible blast-count-independent biological definition and is now diagnosed as MDS, AML-MR, or AML/MDS not otherwise specified depending on blast percentage and genetics. This entry is scoped to the current, TP53-centered AEL/pure erythroid leukemia concept; see `notes` and the classification `discussions` entry for the reclassification history and the ongoing genomic-versus-morphologic debate over where the boundary belongs.

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3
Definitions
7
Pathophys.
1
Histopath.
9
Phenotypes
1
Gaps
24
Pathograph
9
Genes
1
Variants
5
Medical Actions
3
Differentials
1
Trials
3
Models
1
Deep Research
🏷

Classifications

ICD-O Morphology
Leukemia
Harrison's Part
ONCOLOGY HEMATOLOGY
📘

Definitions

3
WHO-HAEM5 acute erythroid leukaemia definition
WHO-HAEM5 restricts AEL to erythroid-predominant marrow (usually >=80% of bone marrow elements) of which >=30% are proerythroblasts, and underscores the central role of biallelic TP53 alterations. AEL cases with somewhat lower erythroid percentage sharing the same clinicopathologic features are still recognized. The diagnosis supersedes AML-MR when its criteria are met.
DIAGNOSTIC_CRITERIA WHO Classification of Haematolymphoid Tumours, fifth edition
Show evidence (3 references)
PMID:35732831 SUPPORT Other
"Diagnostic criteria include erythroid predominance, usually >=80% of bone marrow elements, of which >=30% are proerythroblasts (or pronormoblasts)."
WHO-HAEM5 states the defining marrow-percentage criteria for AEL.
PMID:35732831 SUPPORT Other
"The central role that biallelic TP53 mutations play in this aggressive AML type is underscored"
WHO-HAEM5 emphasizes biallelic TP53 alteration as central to the entity.
PMID:35732831 SUPPORT Other
"The diagnosis of AEL supersedes AML-MR."
WHO-HAEM5 states the diagnostic precedence of AEL over AML-MR.
ICC AML with mutated TP53 definition (pure erythroid leukemia arm)
The ICC does not retain a separately named erythroid-defined entity. Instead it folds pure erythroid leukemia into the broader "AML with mutated TP53" category, unified by TP53 mutation status rather than lineage percentage. This is a materially different classification boundary from WHO-HAEM5, not merely a naming difference.
DIAGNOSTIC_CRITERIA International Consensus Classification 2022
Show evidence (2 references)
PMID:36323674 SUPPORT Other
"By contrast, the 2022 International Consensus Classification (ICC) includes PEL under a broader category of "acute myeloid leukemia with mutated TP53"."
A dedicated PEL case series states the ICC's differing classification boundary relative to WHO.
PMID:36323674 SUPPORT Other
"Pure erythroid leukemia (PEL), also known as acute erythroid leukemia (AEL), is recognized as a distinct morphologic entity by both the 2016 and 2022 World Health Organization (WHO) classification system."
Confirms WHO's continued recognition of a distinct morphologic entity across editions, contrasted with the ICC's TP53-unified approach.
Retired FAB/WHO 2008-2016 erythroid/myeloid (M6a) category
The FAB classification and WHO 2001/2008 editions recognized two AEL subtypes by erythroid/blast percentage alone: "M6a" (erythroid/myeloid, >=50% erythroid cells plus >=20% blasts among non-erythroid cells) and "M6b" (pure erythroid, >=80% erythroid precursors). WHO 2016 eliminated M6a as an AML entity, reclassifying most such cases as MDS, AML-MR, or AML/MDS not otherwise specified based on blast percentage rather than biology; M6b was retained, renamed pure erythroid leukemia, and is the direct ancestor of the current WHO-HAEM5 AEL definition. This history is recorded here so the historical FAB "M6" label is not read as interchangeable with the current, much narrower AEL concept.
DIAGNOSTIC_CRITERIA Historical FAB and WHO 2001/2008 classification (superseded)
Show evidence (3 references)
PMID:30926971 SUPPORT Other
""M6a" cases had at least 50% erythroid cells and at least 20% blasts of non-erythroid cells in bone marrow."
States the historical FAB/WHO 2008 M6a erythroid/myeloid criteria.
PMID:30926971 SUPPORT Other
"M6a was merged into a hybrid subtype of myelodysplasia and AML (specifically, "myelodysplastic syndrome (MDS) or AML, not otherwise specified (NOS) (non-erythroid subtype)" based on the percentage of blasts in the bone marrow rather than biological or genetic features."
Documents the WHO 2016 reclassification of the erythroid/myeloid category into MDS/AML-NOS by blast percentage.
PMID:37246017 SUPPORT Other
"Since the first recognition of an erythroid-predominant hematologic malignancy in the early 20th century, AEL has gone through a turnstile of changing definitions and nomenclature, including eritoleucemia, erythremic myelosis, AML-M6 and pure erythroid leukemia."
A dedicated history review documents the succession of names and definitions culminating in the current entity.
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Discussions and Knowledge Gaps

1
Should AEL/pure erythroid leukemia be defined by erythroid lineage percentage and morphology (the WHO-HAEM5 approach) or unified with other TP53-mutated AML/MDS by genomic profile alone (the position argued by Iacobucci et al. and reflected in part by the ICC)?
CONTROVERSY OPEN ael-classification-boundary-controversy
Attached to
pathophysiology#Biallelic TP53 Inactivation
A comprehensive genomic comparison of AEL against non-erythroid AML and MDS found that the mutational spectrum of AEL is statistically distinct from both, arguing against collapsing AEL into either category on genomic grounds even though TP53 mutation is common to all three. This directly contests the WHO 2016 blast-percentage-driven reclassification of the erythroid/myeloid (M6a) category into MDS, and is in tension with the ICC's decision to fold pure erythroid leukemia into a TP53-unified AML category rather than keep a distinct erythroid entity.
Recorded so this entry does not silently pick one classification vintage as though the boundary were settled; see the `definitions` block for the WHO-HAEM5, ICC, and retired FAB/WHO 2001-2016 positions.
Show evidence (1 reference)
PMID:30926971 SUPPORT Human Clinical
"Thus, mutational prevalence varies significantly between the three major subtypes of myeloid neoplasms (AEL, non-erythroid AML and MDS) in both children and adults, suggesting the recent reclassification of many AEL case as MDS or AML is unfounded from a mutational perspective."
A large genomic cohort argues the mutational spectrum of AEL is distinguishable from MDS and non-erythroid AML, contesting the blast-percentage-only rationale for the WHO 2016 reclassification of the erythroid/myeloid category. Marked PARTIAL because this is one cohort's argument, not a settled resolution, and the current WHO-HAEM5 and ICC positions differ from it in different directions.
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Pathophysiology

7
Biallelic TP53 Inactivation
Nearly all AEL/pure erythroid leukemia cases carry biallelic TP53 alteration, most commonly a missense mutation plus deletion or copy-neutral loss of heterozygosity of the second allele, or two independent clonal TP53 mutations. This is the dominant recurrent lesion in the disease and, per WHO-HAEM5, is central to its current diagnostic definition.
TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee.
Signal Transduction by p53 Class Mediator GO:0072331 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Signal Transduction by p53 Class Mediator (GO:0072331). GO:0072331 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss of p53-Dependent Checkpoint and Apoptotic Control Biallelic loss disables the p53-dependent surveillance that would otherwise arrest, senesce, or eliminate cells with damaged or unstable genomes.
Show evidence (4 references)
PMID:36323674 SUPPORT Human Clinical
"All cases expressed biallelic TP53 alterations, including TP53 deletion/single TP53 mutation (68%), two TP53 mutations (29%) or two TP53 deletions (3%); additional mutations were infrequent."
A 41-case Mayo Clinic series found universal biallelic TP53 alteration in pure erythroid leukemia, with a breakdown of the allelic patterns.
PMID:30926971 SUPPORT Human Clinical
"All but one of the TP53-mutated cases exhibited alterations of both alleles, as two clonal sequence mutations (28.0% of mutated cases), a mutation and DNA copy-neutral loss of heterozygosity (29.0%), or mutation and deletion of the other allele (39%)"
An independent genomic cohort corroborates near-universal biallelic TP53 alteration among TP53-mutated AEL cases and details the three allelic patterns.
PMID:35636055 SUPPORT Human Clinical
"Pure erythroid leukemia (PEL) is a rare acute leukemia with a dismal prognosis. TP53 mutations are a dominant feature of PEL"
A dedicated TP53-in-PEL study states TP53 mutation as the dominant genomic feature of the disease.
+ 1 more reference
Loss of p53-Dependent Checkpoint and Apoptotic Control
With p53 function disabled by biallelic TP53 alteration, the erythroid progenitor clone loses the checkpoint and apoptotic responses that would normally restrain proliferation of a genomically damaged or unstable cell, permitting continued division and accumulation of further genomic lesions.
Negative Regulation of Cell Cycle GO:0045786 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Negative Regulation of Cell Cycle (GO:0045786). GO:0045786 is a biological process from the Gene Ontology. ↓ DECREASED Negative Regulation of Apoptotic Process GO:0043066 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Negative Regulation of Apoptotic Process (GO:0043066). GO:0043066 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
NFIA-ETO2 fusion with cooperating TP53 R248Q (murine erythroblast transplant model) Mouse recapitulates Adding TP53 R248Q to NFIA-ETO2-expressing erythroblasts converts a non-transplantable cell population into a fully penetrant, transplantable pure-erythroid-leukemia-like disease; TP53 R248Q itself does not alter erythroid differentiation but instead confers self-renewal and survival via downregulation of TP53 target genes, directly recapitulating the checkpoint/apoptosis-evasion role modeled at this node.
Downstream
Chromothripsis and Complex or Monosomal Karyotype Loss of p53-dependent genome surveillance permits gross structural genomic catastrophes, including chromothripsis, to persist and be clonally propagated rather than triggering arrest or death.
Show evidence (1 reference)
PMID:36735909 SUPPORT Model Organism
"TP53R248Q does not affect erythroid differentiation but provides self-renewal and survival potential, mostly via downregulation of known TP53 targets."
A mouse model directly separates the TP53-mutant contribution (survival and self-renewal, i.e., checkpoint/apoptosis evasion) from the differentiation-arrest contribution of a cooperating lesion.
Chromothripsis and Complex or Monosomal Karyotype
AEL/pure erythroid leukemia is characterized by extensive karyotypic complexity, including a high rate of chromothripsis (massive, single-event chromosome shattering and reassembly) that is significantly enriched in TP53-mutated cases relative to MDS and non-erythroid AML. Karyotype is complex in essentially all cases and monosomal in the large majority, with deletions in 5q and 7q, monosomy 5/7, trisomy 8, and 17p13 abnormalities (the region containing TP53 itself) among the most common recurrent findings.
DNA Repair GO:0006281 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased DNA Repair (GO:0006281). GO:0006281 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
EPOR/JAK2/STAT5 Signaling Amplification The same structural instability recurrently generates focal gains/amplifications of the EPOR and JAK2 loci, disproportionately in TP53-mutated, erythroid-predominant (pure erythroid leukemia) cases.
Erythroid Maturation Arrest at the Proerythroblast Stage EPOR/JAK2/STAT5 amplification is a proliferative driver in only a subset of TP53-mutated AEL; this parallel edge represents the more general route by which chromosomal instability's other cooperating lesions (e.g., GATA1-complex or epigenetic-regulator dysregulation) reach the maturation-arrest node in cases lacking EPOR/JAK2 involvement.
Show evidence (6 references)
PMID:36323674 SUPPORT Human Clinical
"Karyotype was complex in all cases and monosomal in 90%."
The Mayo Clinic series reports near-universal complex/monosomal karyotype in pure erythroid leukemia.
PMID:38892446 SUPPORT Other
"In the setting of AEL, deletions in 5q and 7q, monosomy 5 and 7, and trisomy 8 are the most common abnormalities detected"
A dedicated AEL review lists the specific recurrent cytogenetic abnormalities within the complex karyotype.
PMID:38892446 SUPPORT Other
"a karyotypic abnormality that may be present on chromosome 17 (17p13) has been linked to the p53 loss of function described in a significant percentage of AEL patients"
Directly connects the recurrent 17p13 cytogenetic abnormality to the TP53 loss-of-function driver modeled upstream in this pathograph.
+ 3 more references
EPOR/JAK2/STAT5 Signaling Amplification
A genetically distinct subset of TP53-mutated AEL, enriched for the pure erythroid phenotype, carries focal gains or amplifications of EPOR and/or JAK2 (sometimes with activating point mutations in either gene), resulting in enhanced STAT5 pathway activation. This erythropoietin-axis signaling amplification is a proliferative driver largely specific to AEL among TP53-mutated myeloid neoplasms and confers even worse prognosis than TP53 mutation alone.
EPOR hgnc:3416 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EPOR (hgnc:3416). hgnc:3416 is a gene from the HUGO Gene Nomenclature Committee. JAK2 hgnc:6192 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves JAK2 (hgnc:6192). hgnc:6192 is a gene from the HUGO Gene Nomenclature Committee.
Erythropoietin-Mediated Signaling Pathway GO:0038162 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Erythropoietin-Mediated Signaling Pathway (GO:0038162). GO:0038162 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
ERG-transduced TP53-mutant hematopoietic stem/progenitor cell transplant model Mouse partially recapitulates Transplanting purified ERG-transduced TP53-mutated hematopoietic stem/progenitor-cell-derived erythroblasts produces fatal erythroleukemia within about 60 days, showing that ERG upregulation - the same ERG/ETS2 locus recurrently co-amplified with EPOR/JAK2 in human AEL - cooperates with TP53 mutation to drive erythroid leukemogenesis.
Downstream
Erythroid Maturation Arrest at the Proerythroblast Stage Amplified erythropoietin-axis signaling drives proliferation of a clonal erythroid population that is concurrently blocked from terminal differentiation by cooperating lesions, favoring expansion of arrested proerythroblasts rather than mature erythroid progeny.
Show evidence (2 references)
PMID:35839275 SUPPORT Human Clinical
"In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in..."
Directly links EPOR/JAK2 lesions to enhanced STAT5 signaling, cell proliferation, and heme-metabolism activity in this subgroup, and to a JAK2-inhibitor-sensitive phenotype.
PMID:35839275 SUPPORT Human Clinical
"These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL."
Establishes that the EPOR/JAK2-amplified subgroup is a prognostically distinct, worse-outcome subset within TP53-mutated AEL.
Erythroid Maturation Arrest at the Proerythroblast Stage
The defining cellular phenotype of AEL is a block in erythroid differentiation at the proerythroblast stage. Mechanistic modeling shows that a cooperating lesion (the pediatric NFIA-ETO2 fusion is the best characterized example) can impair terminal erythroid differentiation by shifting occupancy of erythroid regulatory elements from GATA-motif to ETS-motif-containing target genes, repressing the terminal differentiation program; this differentiation block cooperates with, rather than requires, the TP53-mutant clone's separately conferred survival and self-renewal advantage.
proerythroblast CL:0000547 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proerythroblast (CL:0000547). CL:0000547 is a cell type from the Cell Ontology.
GATA1 hgnc:4170 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATA1 (hgnc:4170). hgnc:4170 is a gene from the HUGO Gene Nomenclature Committee.
Erythrocyte Differentiation GO:0030218 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Erythrocyte Differentiation (GO:0030218). GO:0030218 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
NFIA-ETO2 fusion with cooperating TP53 R248Q (murine erythroblast transplant model) Mouse recapitulates NFIA-ETO2 expression increases proliferation and impairs erythroid differentiation, shifting transcription-factor occupancy from GATA-motif to ETS-motif target genes, recapitulating the GATA1-complex-based maturation-arrest mechanism modeled at this node.
CRISPR/Cas9 Trp53 plus Bcor mutant hematopoietic stem/progenitor cell mouse model Mouse recapitulates Combining Trp53 and Bcor mutations in mouse HSPCs by CRISPR/Cas9 produces AEL-like tumors with a gene-expression profile recapitulating human AEL, including overexpression of the erythroid transcription factors Gata1, Gata2, and Klf1, directly supporting the GATA-complex dysregulation mechanism modeled at this node and linking it to the BCOR cooperating lesion.
Downstream
Erythroid Dysplasia Blockade at the proerythroblast stage yields the dysplastic erythroid morphology (nuclear budding, multinucleation, megaloblastoid change) seen on marrow examination.
Proerythroblast Accumulation and Marrow Replacement Cells blocked at the proerythroblast stage cannot exit the proliferative compartment through terminal differentiation, so the arrested population accumulates in the marrow.
Show evidence (3 references)
PMID:36735909 SUPPORT Model Organism
"NFIA-ETO2 interferes with erythroid differentiation by preferentially binding and repressing erythroid genes that contain NFI binding sites and/or are decorated by ETO2, resulting in a activity shift from GATA- to ETS-motif-containing target genes."
Direct mechanistic evidence in a mouse erythroblast model for how a cooperating fusion lesion produces a differentiation-arrest program through transcriptional-motif redistribution away from the erythroid GATA program.
PMID:36735909 SUPPORT Model Organism
"in the presence of 1 of the most prevalent erythroleukemia-associated mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant clonogenic activity and induced a fully penetrant transplantable PEL-like disease in mice."
Shows the maturation-arrest lesion cooperates with mutant TP53 to produce a fully penetrant pure-erythroid-leukemia-like disease, supporting the causal link modeled here between the two upstream pathophysiology arms and this differentiation-arrest node.
PMID:38892446 SUPPORT Other
"Recent AEL patient transcriptomic data show alterations of transcription or downstream signaling factors that mediate GATA1 activity in more than 25% of the cases"
A dedicated AEL review reports that dysregulation of GATA1 or its transcriptional-complex partners is found in over a quarter of cases, generalizing the maturation-arrest mechanism beyond the single NFIA-ETO2 example.
Proerythroblast Accumulation and Marrow Replacement
Arrested, immature proerythroblasts progressively expand and replace normal trilineage marrow elements, establishing the overt leukemic marrow. De novo AEL and AEL arising after MDS or MDS/MPN share this prominent proerythroblast-proliferation morphology, and the arrested proerythroblast population itself contributes to treatment resistance.
proerythroblast CL:0000547 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves proerythroblast (CL:0000547). CL:0000547 is a cell type from the Cell Ontology.
bone marrow UBERON:0002371 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone marrow (UBERON:0002371). UBERON:0002371 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Leukemia Marrow replacement by a clonal, maturation-arrested erythroid population constitutes the overt acute leukemia phenotype.
Suppression of Normal Hematopoiesis Expansion of the leukemic proerythroblast compartment crowds out and impairs production of normal erythroid, myeloid, and megakaryocytic progeny.
Hepatosplenomegaly Extramedullary spread of the leukemic proerythroblast population to liver and spleen can produce organomegaly.
Evidence of Hemolysis Ineffective erythropoiesis in the dysplastic, arrested erythroid compartment produces laboratory evidence of hemolysis.
Show evidence (3 references)
PMID:35732831 SUPPORT Other
"Proerythroblast have been shown to play an important role in treatment resistance and poor prognosis in AML patients"
WHO-HAEM5 states that proerythroblast burden itself contributes to treatment resistance and poor prognosis, supporting this node as a clinically consequential accumulation rather than a passive bystander population.
PMID:36323674 SUPPORT Human Clinical
"PEL was primary in 14 cases, therapy-related in 14, secondary in 12, and undetermined in one."
Documents that this end-stage marrow-replacement phenotype arises through multiple clinical routes (de novo, therapy-related, and secondary to a prior hematologic disorder), consistent with a shared downstream mechanism reached from different upstream contexts.
PMID:35732831 SUPPORT Other
"De novo AEL and cases that arise following MDS or MDS/MPN share distinctive morphologic features"
WHO-HAEM5 states that de novo and secondary AEL share distinctive morphologic features; the sentence continues by naming prominent proerythroblast proliferation as that feature, correcting a previously mis-cited fragment of the same sentence elsewhere in this file (the source PDF hyphenates "proerythroblast" across a line break, so the quote stops short of that word rather than risk an inexact substring match).
Suppression of Normal Hematopoiesis
The leukemic marrow environment suppresses normal trilineage hematopoiesis, producing the pancytopenia (anemia, thrombocytopenia, neutropenia) that dominates the clinical presentation and drives infectious and bleeding complications.
bone marrow UBERON:0002371 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bone marrow (UBERON:0002371). UBERON:0002371 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Anemia Reduced normal erythroid output lowers circulating red-cell mass.
Thrombocytopenia Reduced normal megakaryocytic output lowers the platelet count.
Neutropenia Reduced normal granulocytic output lowers the mature neutrophil count.
Show evidence (1 reference)
PMID:30926971 SUPPORT Other
"AEL is characterized by proliferation of erythroid and myeloid blast cells in the bone marrow and is associated with a poor prognosis"
States the marrow-based, proliferative-blast character of AEL that underlies subsequent normal-hematopoiesis suppression.
✶

Histopathology

1
Proerythroblast-Predominant Marrow with Marked Dyserythropoiesis
Bone marrow shows erythroid predominance (usually >=80% of marrow elements) of which >=30% are proerythroblasts/pronormoblasts, with marked dyserythropoiesis (nuclear budding, multinucleation, megaloblastoid change) that can be difficult to distinguish morphologically from severe reactive dyserythropoiesis.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"Diagnostic criteria include erythroid predominance, usually >=80% of bone marrow elements, of which >=30% are proerythroblasts (or pronormoblasts)."
WHO-HAEM5 states the diagnostic marrow morphology criteria.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acute Erythroid Leukemia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Blood 5
Leukemia HP:0001909 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukemia (HP:0001909). HP:0001909 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"Acute erythroid leukaemia (AEL) (previously pure erythroid leukaemia, an acceptable related term in this edition) is a distinct AML type characterized by neoplastic proliferation of erythroid cells with features of maturation arrest and high prevalence of biallelic TP53 alterations."
WHO-HAEM5 establishes AEL as a distinct AML/leukemia entity.
Anemia OBLIGATE HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Sequelae: Pallor
Show evidence (2 references)
PMID:38892446 SUPPORT Human Clinical
"the most prominent symptoms and findings at diagnosis are fever and pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and evidence of hemolysis"
Directly names anemia, with a median hemoglobin figure, as one of the most prominent findings at AEL diagnosis.
PMID:36323674 SUPPORT Human Clinical
"All 40 patients with an available complete blood cell count presented with anemia (100%), essentially all with thrombocytopenia (98%) and 63% with neutropenia"
All 40 evaluable Mayo Clinic patients had anemia (100%), placing it in the OBLIGATE band.
Thrombocytopenia VERY_FREQUENT HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36323674 SUPPORT Human Clinical
"All 40 patients with an available complete blood cell count presented with anemia (100%), essentially all with thrombocytopenia (98%) and 63% with neutropenia"
98% of evaluable Mayo Clinic patients had thrombocytopenia, placing it in the VERY_FREQUENT band (80-99%).
Neutropenia FREQUENT Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36323674 SUPPORT Human Clinical
"All 40 patients with an available complete blood cell count presented with anemia (100%), essentially all with thrombocytopenia (98%) and 63% with neutropenia"
63% of evaluable Mayo Clinic patients had neutropenia, placing it in the FREQUENT band (30-79%).
Evidence of Hemolysis Hemolytic anemia HP:0001878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Evidence of hemolysis, annotated with Hemolytic anemia (HP:0001878). HP:0001878 is a phenotype from the Human Phenotype Ontology.
HP:0001878 (Hemolytic anemia) is the closest available term but is slightly stronger than the source's "evidence of hemolysis" (e.g. elevated bilirubin/LDH, reduced haptoglobin), which does not itself assert a diagnosis of hemolytic anemia.
Show evidence (1 reference)
PMID:38892446 SUPPORT Human Clinical
"the most prominent symptoms and findings at diagnosis are fever and pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and evidence of hemolysis"
Names evidence of hemolysis as one of the most prominent findings at AEL diagnosis.
Cardiovascular 1
Hepatosplenomegaly HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38892446 SUPPORT Human Clinical
"the most prominent symptoms and findings at diagnosis are fever and pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and evidence of hemolysis"
Names hepatosplenomegaly as one of the most prominent findings at AEL diagnosis.
Integument 1
Pallor HP:0000980 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pallor (HP:0000980). HP:0000980 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38892446 SUPPORT Human Clinical
"the most prominent symptoms and findings at diagnosis are fever and pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and evidence of hemolysis"
Names pallor as one of the most prominent findings at AEL diagnosis.
Metabolism 1
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38892446 SUPPORT Human Clinical
"the most prominent symptoms and findings at diagnosis are fever and pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and evidence of hemolysis"
Names fever as one of the most prominent findings at AEL diagnosis.
Other 1
Erythroid Dysplasia HP:0031688 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Erythroid dysplasia (HP:0031688). HP:0031688 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38892446 SUPPORT Other
"the most typical features in the bone marrow biopsy are hypercellularity, dyserythropoiesis, and a high percentage of erythroid precursors"
A dedicated AEL review names dyserythropoiesis directly as one of the most typical bone-marrow findings, supporting this phenotype. Replaces a previously mis-cited fragment of a WHO-HAEM5 sentence that, in full, described proerythroblast proliferation rather than dysplasia.
🧬

Genetic Associations

9
TP53 (Central, near-universal somatic driver lesion; biallelic alteration is characteristic of the disease)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC
Variants (1)
Biallelic TP53 alteration (mutation plus deletion/LOH, or two mutations)
Gene: TP53 hgnc:11998 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TP53 (hgnc:11998). hgnc:11998 is a gene from the HUGO Gene Nomenclature Committee. biallelic alteration
Biallelic TP53 alteration occurs through one of three patterns: a single missense/nonsense mutation combined with deletion of the other allele, a single mutation combined with copy-neutral loss of heterozygosity, or two independent clonal mutations. Missense mutations predominate and are most often in the DNA-binding domain.
Functional effects
p53-dependent checkpoint and apoptotic signaling loss of function
Biallelic loss-of-function alteration abolishes p53-dependent surveillance of genomic damage.
Show evidence (1 reference)
PMID:30926971 SUPPORT Human Clinical
"All but one of the TP53-mutated cases exhibited alterations of both alleles, as two clonal sequence mutations (28.0% of mutated cases), a mutation and DNA copy-neutral loss of heterozygosity (29.0%), or mutation and deletion of the other allele (39%)"
Establishes the three recurrent biallelic-alteration patterns and their relative frequency.
EPOR (Recurrent focal amplification defining a poor-prognosis, pure-erythroid-phenotype subset of TP53-mutated AEL)
Gene: EPOR hgnc:3416 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EPOR (hgnc:3416). hgnc:3416 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:35839275 SUPPORT Human Clinical
"we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia"
Establishes EPOR amplification as a recurrent cooperating lesion enriched in the pure-erythroid, TP53-mutated subgroup.
JAK2 (Recurrent focal amplification, and occasional activating mutation, cooperating with TP53 loss and EPOR amplification)
Gene: JAK2 hgnc:6192 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is JAK2 (hgnc:6192). hgnc:6192 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:35839275 SUPPORT Human Clinical
"These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL."
Establishes the JAK2/EPOR-amplified subgroup as prognostically distinct within TP53-mutated AEL.
GATA1 (Recurrent dysregulation of the GATA1 transcriptional complex, either directly or via its interacting partners, underlying the erythroid maturation arrest)
Gene: GATA1 hgnc:4170 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GATA1 (hgnc:4170). hgnc:4170 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (2 references)
PMID:38892446 SUPPORT Model Organism
"Ectopic expression of these physical or functional interactors of the GATA1 transcriptional complexes (ERG, ETO2, SKI, and SPI1) in murine erythroid progenitors resulted in decreased chromatin accessibility at GATA1-binding sites and promoted proliferation with the immature phenotype"
A review of mouse-model data shows that ectopic expression of GATA1 transcriptional-complex interactors reduces accessibility at GATA1-binding sites and drives an immature, proliferative erythroid phenotype, mechanistically supporting GATA1-complex disruption as a route to the maturation-arrest node.
DOI:10.1097/hs9.0000000000000558 SUPPORT Other
"the pathogenesis of the disease is based on the interplay between signaling mutations, impaired TP53 function, and altered chromatin organization. These alterations lead to aberrant activity of erythroid transcriptional master regulators like GATA1"
A dedicated review of AEL molecular models synthesizes human genetics and mouse-model data to the same conclusion: signaling mutations, impaired TP53 function, and chromatin dysregulation converge on aberrant GATA1 activity.
TET2 (Recurrent cooperating epigenetic-regulator mutation)
Gene: TET2 hgnc:25941 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TET2 (hgnc:25941). hgnc:25941 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:38892446 SUPPORT Human Clinical
"DNA methylation plays an essential role in erythroid malignancies, and it is regulated by several factors, including TET2 and DNMT3A/B"
Establishes TET2's mechanistic role in the DNA-methylation dysregulation implicated in AEL.
ASXL1 (Recurrent cooperating epigenetic-regulator mutation)
Gene: ASXL1 hgnc:18318 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ASXL1 (hgnc:18318). hgnc:18318 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
IDH2 (Recurrent cooperating epigenetic-regulator mutation)
Gene: IDH2 hgnc:5383 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is IDH2 (hgnc:5383). hgnc:5383 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
DNMT3A (Recurrent cooperating epigenetic-regulator mutation)
Gene: DNMT3A hgnc:2978 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNMT3A (hgnc:2978). hgnc:2978 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (1 reference)
PMID:38892446 SUPPORT Human Clinical
"DNA methylation plays an essential role in erythroid malignancies, and it is regulated by several factors, including TET2 and DNMT3A/B"
Establishes DNMT3A's mechanistic role in the DNA-methylation dysregulation implicated in AEL.
BCOR (Recurrent cooperating epigenetic-regulator mutation linked to treatment resistance)
Gene: BCOR hgnc:20893 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BCOR (hgnc:20893). hgnc:20893 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING variant_origin: SOMATIC
Show evidence (2 references)
PMID:35015684 SUPPORT In Vitro
"highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby selectively unlinking the RING-PCGF enzymatic core from the chromatin-targeting auxiliary subcomplex"
Establishes the mechanistic consequence of BCOR mutation (loss of PRC1.1 repressive function) in leukemia cell-line and patient-sample systems.
PMID:35015684 SUPPORT In Vitro
"BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive activity, leading to epigenetic reprogramming and transcriptional activation at target loci"
States the specific epigenetic-reprogramming mechanism by which BCOR mutation drives aberrant transcription.
💊

Medical Actions

5
Hypomethylating Agent Plus Venetoclax
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: azacitidine CHEBI:2038 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azacitidine, annotated with 5-azacytidine (CHEBI:2038). CHEBI:2038 is a therapeutic agent from Chemical Entities of Biological Interest. venetoclax CHEBI:133021 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses venetoclax (CHEBI:133021). CHEBI:133021 is a therapeutic agent from Chemical Entities of Biological Interest.
Combination therapy with a hypomethylating agent (azacitidine or decitabine) and the BCL-2 inhibitor venetoclax is the most commonly used regimen in reported AEL/pure erythroid leukemia series, reflecting its broader use in TP53-mutated and older/unfit AML. Reported outcomes remain poor: in one series no responses or allogeneic transplants were achieved regardless of regimen.
Show evidence (4 references)
PMID:36323674 SUPPORT Human Clinical
"Treatment details were available in 29 patients: hypomethylating agent (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy (n = 4), supportive care/other (n = 8)"
Documents HMA + venetoclax as the most frequently used regimen among treated patients in this series.
PMID:36323674 SUPPORT Human Clinical
"no responses or allogeneic stem cell transplants were documented, and all patients died at a median 1.8 months (range 0.2-9.3)."
Reports the outcome across all treatment approaches in this series, establishing that current regimens are largely ineffective rather than overstating any single regimen's benefit.
PMID:38892446 SUPPORT Other
"erythroid/megakaryocytic AML subtypes are associated with resistance to venetoclax"
States the specific venetoclax-resistance association in erythroid/megakaryocytic AML subtypes such as AEL.
+ 1 more reference
Intensive Cytarabine-Based Chemotherapy
Action: ChemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. NCIT:C15632
Agent: cytarabine CHEBI:28680 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cytarabine (CHEBI:28680). CHEBI:28680 is a therapeutic agent from Chemical Entities of Biological Interest.
Intensive induction chemotherapy analogous to standard AML regimens is used in a minority of patients, generally younger or fitter ones, but has not been shown to produce durable responses in reported AEL/pure erythroid leukemia series.
Show evidence (2 references)
PMID:36323674 SUPPORT Human Clinical
"Treatment details were available in 29 patients: hypomethylating agent (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy (n = 4), supportive care/other (n = 8)"
Documents intensive chemotherapy as one of the treatment approaches used, though in a minority of patients.
PMID:38892446 SUPPORT Human Clinical
"The objective response rate (ORR) was 72%, according to the ELN criteria. Complete response (CR) occurred in 79 patients (66%), partial response (PR) in 7 (6%), stable disease (SD) in 16 (13%), and primary disease progression (PPD) in 17 (14%)."
A 217-patient multinational cohort reports substantial response rates to intensive chemotherapy; marked PARTIAL because this cohort applied older, less stringent AEL definitions and so overlaps what would now be classified as MDS or other AML, per the same review.
Allogeneic Hematopoietic Cell Transplantation
Action: Hematopoietic Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. NCIT:C15431
Allogeneic hematopoietic cell transplantation (allo-HCT), typically as consolidation after remission induction, is the only treatment approach reported to be potentially curative in AEL/pure erythroid leukemia. Achieving the deep remission required to proceed to transplant is itself a major challenge in this TP53-driven, chemoresistant disease, so only a minority of patients reach transplant.
Show evidence (3 references)
PMID:38892446 SUPPORT Human Clinical
"Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach for AEL, but it requires deep remission of the disease, which is rarely achieved in these patients"
States that allo-HCT is the only potentially curative approach, and names the deep-remission requirement that limits how many patients reach it.
PMID:38892446 SUPPORT Human Clinical
"The median OS of AlloBMT recipients was 89 months, compared to 5 months for those who did not undergo AlloBMT"
Reports a large survival benefit for patients who reach transplant versus those who do not, in a cohort study cited by this review; this is a selected-population comparison (transplant eligibility itself correlates with fitness and remission depth) rather than a randomized estimate of transplant's isolated effect. The cohort also used the 2008 WHO classification of AEL, broader than the current WHO-HAEM5 definition used in this entry, so the magnitude should not be assumed to transfer unchanged to TP53-biallelic-restricted modern AEL.
PMID:38892446 SUPPORT Human Clinical
"the definition of AEL for this analysis was based on the 2008 WHO classification"
States the classification-vintage caveat directly; marked PARTIAL because it qualifies rather than supports the 89-vs-5-month claim on its own.
Investigational JAK Inhibition in EPOR/JAK2-Amplified Disease
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ruxolitinib CHEBI:66919 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ruxolitinib (CHEBI:66919). CHEBI:66919 is a therapeutic agent from Chemical Entities of Biological Interest.
In preclinical models, AEL cases with EPOR and/or JAK2 gain/amplification show high sensitivity to the JAK1/2 inhibitor ruxolitinib in vitro and in patient-derived xenografts, suggesting a targeted therapeutic strategy for this molecularly defined subgroup. This is model-system evidence and has not been established as a standard clinical treatment.
Mechanism Target:
INHIBITS EPOR/JAK2/STAT5 Signaling Amplification — Ruxolitinib inhibits JAK1/2 kinase activity, blocking the amplified EPOR/JAK2-driven STAT5 signaling that this subgroup depends on.
Show evidence (1 reference)
PMID:35839275 SUPPORT Model Organism
"Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions."
States the preclinical (patient-derived xenograft and cell culture) basis for JAK2 inhibition as a possible targeted approach in this genomically defined subgroup; evidence_source is MODEL_ORGANISM because the response data are from xenograft and cell-line models, not treated patients.
Best Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Given the dismal response to available regimens, many patients, particularly those unfit for intensive or hypomethylating-agent-based therapy, are managed with supportive care (transfusion support, infection prophylaxis/treatment) alone.
Show evidence (1 reference)
PMID:36323674 SUPPORT Human Clinical
"Treatment details were available in 29 patients: hypomethylating agent (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy (n = 4), supportive care/other (n = 8)"
Documents supportive care/other as a treatment approach used in nearly a third of treated patients in this series.
🔬

Diagnosis

2
Bone Marrow Immunophenotyping (CD71-Positive, Myeloid-Marker-Negative Pattern)
Immunohistochemistry and flow cytometry characterize the malignant erythroid population and exclude a myeloid-lineage blast population.
bone marrow flow cytometry NCIT:C38063 NCI Thesaurus (NCIT)
Markers: CD71-positive (often overexpressed); may also express Gerbich antigens, E-cadherin, carbonic anhydrase 1, CD36, CD68, and dim hemoglobin/glycophorin A; myeloperoxidase, HLA-DR, and CD33 typically negative in the majority of cells; CD13 and CD117 are variable.
Show evidence (2 references)
PMID:38892446 SUPPORT Other
"CD71 is a surface transferrin receptor that is present on most erythroid progenitors and is typically overexpressed in AEL blasts and erythroid malignant precursors"
States the CD71-positive marker pattern characterizing the malignant erythroid population.
PMID:38892446 SUPPORT Other
"Myeloperoxidase, HLA-DR, and CD33, which are known markers of myeloid lineage, are typically negative in the majority of cells in the biopsy"
States the myeloid-marker-negative pattern that helps exclude a non-erythroid AML immunophenotype.
Bone Marrow Aspirate and Biopsy Morphology
Bone marrow biopsies in AEL are frequently suboptimal (dry tap or hemodiluted aspirate), so core biopsy and immunohistochemistry are often required alongside aspirate morphology to establish the diagnosis.
bone marrow biopsy NCIT:C15193 NCI Thesaurus (NCIT)
Results: Hypercellularity, dyserythropoiesis, and a high percentage of erythroid precursors.
Show evidence (1 reference)
PMID:38892446 SUPPORT Other
"the most typical features in the bone marrow biopsy are hypercellularity, dyserythropoiesis, and a high percentage of erythroid precursors"
States the core morphologic bone-marrow findings used in diagnosis.
📈

Progression

2
Diagnosis and TP53/Cytogenetic Risk Assessment
Diagnosis requires marrow morphology meeting the current WHO-HAEM5 erythroid-predominance/proerythroblast threshold plus TP53 mutation testing and karyotype, since biallelic TP53 alteration and complex/monosomal karyotype are near-universal and central to both diagnosis and prognosis. EPOR/JAK2 status may further stratify a molecularly distinct, especially poor-prognosis subgroup.
Show evidence (1 reference)
PMID:35732831 SUPPORT Other
"The central role that biallelic TP53 mutations play in this aggressive AML type is underscored"
WHO-HAEM5 places TP53 status at the center of the diagnostic and prognostic framework for this disease.
Rapid Clinical Decline Despite Treatment
Reported outcomes are extremely poor overall. A 41-case, entirely TP53-biallelic Mayo Clinic series treated across the modern HMA/HMA plus venetoclax/intensive-chemotherapy/supportive-care spectrum saw no responses or transplants and a median survival of 1.8 months. A larger, more heterogeneous 217-patient multinational cohort using older definitions reported a longer median overall survival, and the small subset of patients who reached allogeneic transplant fared substantially better than those who did not (see the Allogeneic Hematopoietic Cell Transplantation treatment entry) - underscoring that reaching deep remission and transplant, not any single drug regimen, is the main outcome-modifying factor identified so far.
Show evidence (3 references)
PMID:36323674 SUPPORT Human Clinical
"no responses or allogeneic stem cell transplants were documented, and all patients died at a median 1.8 months (range 0.2-9.3)."
Documents the extremely poor outcome across treatment approaches in this series.
PMID:37246017 SUPPORT Other
"These cytogenetic and molecular characteristics render current treatment approaches largely ineffective, and signal an urgent need for novel therapeutic modalities."
A dedicated review corroborates that current treatment approaches are largely ineffective given the disease's cytogenetic/molecular characteristics.
PMID:38892446 SUPPORT Human Clinical
"The median OS of AlloBMT recipients was 89 months, compared to 5 months for those who did not undergo AlloBMT"
Shows that reaching allogeneic transplant, rather than any particular drug regimen, is associated with markedly longer survival in a larger, more heterogeneous cohort than the Mayo series.
📊

Prevalence

1
Reported AML case series (AEL as a proportion of all AML)
Unknown Ultra Rare
AEL/pure erythroid leukemia accounts for approximately 0.5% to 1.5% of all AML cases in reported series; this is a proportion of diagnosed AML, not a general-population prevalence rate, so no rate_per_100000 is given. Reported cohorts have a median diagnosis age of approximately 67 years (with some evidence of a bimodal distribution, a smaller peak around age 20) and a male-to-female ratio of approximately 2.4:1.
Show evidence (3 references)
PMID:35839275 SUPPORT Other
"acute erythroid leukemia (AEL) represents a rare subtype of acute myeloid leukemia (AML), accounting for 0.5% to 1.5% of AML cases"
States the proportion of AML cases represented by AEL.
PMID:38892446 SUPPORT Human Clinical
"The median age of AEL diagnosis is 67 years old, though some studies have demonstrated a bimodal age of diagnosis with a small peak at around 20 years old and a larger second peak in the early 70s."
States the median diagnosis age and bimodal age distribution.
PMID:38892446 SUPPORT Human Clinical
"This disease also demonstrates a slight male-to-female predominance (2.4:1)"
States the male-to-female sex ratio.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Acute Erythroid Leukemia:

Erythroid Hyperplasia in Megaloblastic Anemia Not Yet Curated MONDO:0001700
Overlapping Features Severe vitamin B12 or folate deficiency produces marked erythroid hyperplasia with megaloblastic, sometimes strikingly atypical, erythroid precursors that can superficially resemble the dysplastic proerythroblast proliferation of AEL. Unlike AEL, this is a reactive, non-clonal process driven by ineffective erythropoiesis and intramedullary destruction of defective erythroid precursors, and it resolves with B12/folate repletion rather than requiring leukemia-directed therapy.
Distinguishing Features
  • Megaloblastic marrow lacks biallelic TP53 alteration and complex/monosomal karyotype, unlike AEL/pure erythroid leukemia.
  • Erythroid precursors show classic megaloblastic nuclear-cytoplasmic asynchrony rather than the proerythroblast-predominant dysplasia of AEL.
  • Low serum B12/folate, elevated methylmalonic acid and/or homocysteine, and rapid, complete hematologic resolution with vitamin repletion confirm the diagnosis.
Show evidence (1 reference)
PMID:19094231 SUPPORT Human Clinical
"Concurrent hemolysis in patients with vitamin B12 deficiency is a well-recognized phenomenon and has been attributed to intramedullary destruction of erythrocytes (ineffective erythropoiesis)."
Supports the reactive, ineffective-erythropoiesis basis of the erythroid hyperplasia seen in B12 deficiency, distinguishing its mechanism from the clonal, TP53-driven proliferation of AEL.
Congenital Dyserythropoietic Anemia MONDO:0019403
Overlapping Features The congenital dyserythropoietic anemias (CDAs) are inherited disorders of erythroid differentiation/proliferation that produce dysplastic erythroid precursors (multinuclearity, internuclear chromatin bridging) and ineffective erythropoiesis, morphologically overlapping with the dyserythropoiesis of AEL but arising from germline variants rather than an acquired, TP53-driven clonal leukemic process.
Distinguishing Features
  • CDA presents from infancy/childhood with a chronic, non-progressive course and a specific germline genetic cause (e.g., CDAN1, SEC23B, KLF1), without biallelic TP53 alteration, complex karyotype, or blast excess.
  • CDA shows characteristic ultrastructural findings (e.g., binuclearity, chromatin bridges, or a spongy heterochromatin pattern depending on type), whereas AEL shows leukemic proerythroblast-predominant dysplasia.
  • AEL is acquired, typically presents in older adults, and carries the TP53/cytogenetic abnormalities characteristic of clonal leukemia.
Show evidence (2 references)
PMID:32702750 SUPPORT Other
"Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of inherited anemias that affect the normal differentiation-proliferation pathways of the erythroid lineage."
Defines CDA as an inherited erythroid differentiation disorder, the key distinction from acquired, clonal AEL.
PMID:32702750 SUPPORT Other
"They belong to the wide group of ineffective erythropoiesis conditions that mainly result in monolinear cytopenia."
Characterizes CDA as an ineffective-erythropoiesis, monolinear-cytopenia disorder rather than a leukemic marrow-replacement process.
Myelodysplastic Syndrome with Erythroid Predominance MONDO:0018881
Overlapping Features Myelodysplastic syndrome can present with marked erythroid hyperplasia and dysplasia, and this is precisely the diagnostic space the retired "erythroid/myeloid" (M6a) AEL category was reclassified into under WHO 2016: cases with erythroid predominance but blast counts and biology below the current AEL threshold are now diagnosed as MDS rather than AEL.
Distinguishing Features
  • Diagnosis turns on the current WHO-HAEM5 blast/proerythroblast thresholds (AEL requires marked erythroid predominance with >=30% proerythroblasts).
  • Biallelic TP53 alteration with complex/monosomal karyotype favors AEL/pure erythroid leukemia, while lower blast counts, non-TP53 MDS-typical mutations (e.g., SF3B1, ASXL1), and a more indolent course favor MDS.
  • The ICC's TP53-unified "AML with mutated TP53" category and the ongoing genomic-versus-morphologic classification debate (see `discussions`) mean this boundary is actively contested rather than fixed.
Show evidence (2 references)
PMID:30926971 SUPPORT Other
"M6a was merged into a hybrid subtype of myelodysplasia and AML (specifically, "myelodysplastic syndrome (MDS) or AML, not otherwise specified (NOS) (non-erythroid subtype)" based on the percentage of blasts in the bone marrow rather than biological or genetic features."
Documents the specific reclassification of erythroid-predominant, lower-blast cases into MDS/AML-NOS; this is a classification-history statement rather than a primary clinical-cohort finding, so evidence_source is OTHER (matching the other citation of this same sentence elsewhere in this file).
PMID:30926971 SUPPORT Human Clinical
"MDS-associated mutations such as SF3B1 and ASXL1 were less frequent in AEL compared to MDS"
Provides a molecular distinguishing feature (relative depletion of classic MDS-driver mutations in AEL) supporting differentiation from MDS.
🔬

Clinical Trials

1
NCT02861651 NOT_APPLICABLE COMPLETED
Observational molecular-characterization study using array comparative genomic hybridization and targeted next-generation sequencing of 106 myeloid/erythrocyte-differentiation genes in 40 cases of the older, broader erythroid/myeloid (M6a) AEL subtype, aiming to determine whether M6a-AML constitutes a distinct AML class and to document the basis for its poor prognosis. Predates WHO-HAEM5 and does not target the TP53-biallelic, pure-erythroid-restricted entity scoped by this file.
Show evidence (1 reference)
clinicaltrials:NCT02861651 SUPPORT Other
"the investigators will search for molecular alterations in 40 M6a-AMLs using array comparative genomic hybridization (aCGH) and next-generation sequencing (NGS) of 106 genes known or suspected to have a role in myeloid malignancies or in erythrocyte differentiation."
States the trial's molecular-characterization objective and design; observational, so evidence_source is OTHER rather than a treatment-outcome classification.
🐁

Animal Models

3
NFIA-ETO2 fusion with cooperating TP53 R248Q (murine erythroblast transplant model)
Species
Mouse
Genotype
t(1;16)(p31;q24) NFIA-ETO2 fusion expressed in murine erythroleukemia cells and primary fetal-liver-derived erythroblasts, with or without cooperating Trp53 R248Q
Publication
PMID:36735909
Pathograph links
Erythroid Maturation Arrest at the Proerythroblast Stage recapitulates fidelity: moderate NFIA-ETO2 expression increases proliferation and impairs erythroid differentiation, shifting transcription-factor occupancy from GATA-motif to ETS-motif target genes, recapitulating the GATA1-complex-based maturation-arrest mechanism modeled at this node.
Limitations: The t(1;16)(p31;q24) NFIA-ETO2 fusion has so far been reported exclusively in pediatric pure erythroid leukemia, so this model specifically supports the maturation-arrest mechanism in that rare genetic subgroup, not the TP53-driven adult-onset disease that dominates AEL case series.
Readouts
Erythroid differentiation and proliferation of NFIA-ETO2-expressing erythroblasts
Direction: DECREASED
Interpretation: Direct measurement of impaired terminal erythroid differentiation caused by the fusion.
Show evidence (1 reference)
PMID:36735909 SUPPORT Model Organism
"NFIA-ETO2 significantly increased proliferation and impaired erythroid differentiation of murine erythroleukemia cells and of primary fetal liver-derived EBs."
Direct readout of the differentiation-arrest phenotype in the mouse model.
Show evidence (1 reference)
PMID:36735909 SUPPORT Model Organism
"NFIA-ETO2 interferes with erythroid differentiation by preferentially binding and repressing erythroid genes that contain NFI binding sites and/or are decorated by ETO2, resulting in a activity shift from GATA- to ETS-motif-containing target genes."
Establishes the model as informative for the GATA-to-ETS transcriptional mechanism modeled at this node.
Loss of p53-Dependent Checkpoint and Apoptotic Control recapitulates fidelity: high Adding TP53 R248Q to NFIA-ETO2-expressing erythroblasts converts a non-transplantable cell population into a fully penetrant, transplantable pure-erythroid-leukemia-like disease; TP53 R248Q itself does not alter erythroid differentiation but instead confers self-renewal and survival via downregulation of TP53 target genes, directly recapitulating the checkpoint/apoptosis-evasion role modeled at this node.
Limitations: A single hotspot TP53 allele (R248Q) was used; whether every biallelic TP53 alteration pattern seen in human AEL confers an equivalent self-renewal advantage in this system was not tested.
Readouts
Clonogenic activity and transplantability of NFIA-ETO2 plus TP53 R248Q erythroblasts
Direction: INCREASED
Interpretation: TP53 R248Q converts the fusion-alone phenotype into a transplantable leukemia, evidencing a survival/self-renewal gain rather than a differentiation effect.
Show evidence (1 reference)
PMID:36735909 SUPPORT Model Organism
"in the presence of 1 of the most prevalent erythroleukemia-associated mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant clonogenic activity and induced a fully penetrant transplantable PEL-like disease in mice."
Direct readout of transplantable-leukemia induction attributable to the TP53 mutation.
Show evidence (1 reference)
PMID:36735909 SUPPORT Model Organism
"TP53R248Q does not affect erythroid differentiation but provides self-renewal and survival potential, mostly via downregulation of known TP53 targets."
Directly separates the TP53-mutant contribution (checkpoint/apoptosis evasion) from the differentiation-arrest contribution of NFIA-ETO2.
CRISPR/Cas9 Trp53 plus Bcor mutant hematopoietic stem/progenitor cell mouse model
Species
Mouse
Genotype
CRISPR/Cas9-induced Trp53 and Bcor mutations in hematopoietic stem/progenitor cells
Publication
PMID:38892446
Pathograph links
Erythroid Maturation Arrest at the Proerythroblast Stage recapitulates fidelity: moderate Combining Trp53 and Bcor mutations in mouse HSPCs by CRISPR/Cas9 produces AEL-like tumors with a gene-expression profile recapitulating human AEL, including overexpression of the erythroid transcription factors Gata1, Gata2, and Klf1, directly supporting the GATA-complex dysregulation mechanism modeled at this node and linking it to the BCOR cooperating lesion.
Limitations: Reported here via a secondary review description rather than the primary study, so experimental detail (penetrance, latency, additional cooperating events) cannot be independently verified in this entry.
Show evidence (1 reference)
PMID:38892446 SUPPORT Model Organism
"Mouse AEL tumors established by CRISPR/Cas9 of HSPCs with Trp53 and Bcor mutations had a gene expression profile recapitulating human AEL tumors with an overexpression of erythroid transcription factors such as Gata1, Gata2, and Klf1"
A review reports this mouse-model finding; marked PARTIAL because the review is a secondary source for the primary experimental result.
ERG-transduced TP53-mutant hematopoietic stem/progenitor cell transplant model
Species
Mouse
Genotype
Retroviral ERG overexpression in TP53-mutated hematopoietic stem/progenitor cells
Publication
PMID:38892446
Pathograph links
EPOR/JAK2/STAT5 Signaling Amplification partially recapitulates fidelity: low Transplanting purified ERG-transduced TP53-mutated hematopoietic stem/progenitor-cell-derived erythroblasts produces fatal erythroleukemia within about 60 days, showing that ERG upregulation - the same ERG/ETS2 locus recurrently co-amplified with EPOR/JAK2 in human AEL - cooperates with TP53 mutation to drive erythroid leukemogenesis.
Limitations: This model tests retroviral ERG overexpression alone, not the focal EPOR/JAK2/ERG co-amplification event seen in human AEL, and evidence is drawn from a secondary review description rather than the primary study, so mechanistic detail (dose, kinetics, STAT5 pathway involvement specifically) cannot be independently verified here.
Show evidence (1 reference)
PMID:38892446 SUPPORT Model Organism
"transplanting purified ERG-transduced TP53-mutated HSPC erythroblasts resulted in fatal erythroleukemia within 60 days"
A review reports this mouse transplant finding; marked PARTIAL because the review is a secondary source for the primary experimental result and does not report STAT5 pathway activation specifically for this model.
{ }

Source YAML

click to show 
name: Acute Erythroid Leukemia
creation_date: "2026-08-26T00:00:00Z"
description: >-
  Acute erythroid leukemia (AEL, MONDO:0017858; historically FAB M6) is a rare
  acute myeloid leukemia subtype defined by a predominant, maturation-arrested
  erythroid population with marked dyserythropoiesis. Classification has moved
  substantially and is scoped narrowly here. WHO-HAEM5 (2022) restricts AEL to
  what was previously called pure erythroid leukemia: erythroid predominance
  (usually >=80% of bone marrow elements) of which >=30% are proerythroblasts,
  with a high prevalence of biallelic TP53 alterations; the diagnosis
  supersedes AML with myelodysplasia-related changes (AML-MR). The ICC (2022)
  reaches a closely related but not identical position, folding pure erythroid
  leukemia into the broader "AML with mutated TP53" category rather than
  keeping a separate erythroid-defined entity. Both classifications retired
  the older, broader "erythroleukemia" (myeloid/erythroid, FAB M6a) category,
  which lacked a reproducible blast-count-independent biological definition
  and is now diagnosed as MDS, AML-MR, or AML/MDS not otherwise specified
  depending on blast percentage and genetics. This entry is scoped to the
  current, TP53-centered AEL/pure erythroid leukemia concept; see `notes` and
  the classification `discussions` entry for the reclassification history and
  the ongoing genomic-versus-morphologic debate over where the boundary
  belongs.
categories:
- Hematologic Malignancy
- Acute Leukemia
- Molecularly Defined Cancer
parents:
- acute myeloid leukemia
disease_term:
  preferred_term: acute erythroid leukemia
  term:
    id: MONDO:0017858
    label: acute erythroid leukemia
classifications:
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:35732831
      reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Acute erythroid leukaemia (AEL) (previously pure erythroid leukaemia,
        an acceptable related term in this edition) is a distinct AML type
        characterized by neoplastic proliferation of erythroid cells with
        features of maturation arrest and high prevalence of biallelic TP53
        alterations.
      explanation: >-
        WHO-HAEM5 places AEL as a distinct type within the AML family,
        supporting placement in Harrison's oncology/hematology Part.
  icdo_morphology:
    classification_value: Leukemia
    evidence:
    - reference: PMID:35732831
      reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The diagnosis of AEL supersedes AML-MR.
      explanation: >-
        WHO-HAEM5 confirms AEL as a leukemia (not a myelodysplastic) diagnosis
        that takes precedence over the AML-MR category when its criteria are
        met.
definitions:
- name: WHO-HAEM5 acute erythroid leukaemia definition
  definition_type: DIAGNOSTIC_CRITERIA
  scope: WHO Classification of Haematolymphoid Tumours, fifth edition
  description: >-
    WHO-HAEM5 restricts AEL to erythroid-predominant marrow (usually >=80% of
    bone marrow elements) of which >=30% are proerythroblasts, and underscores
    the central role of biallelic TP53 alterations. AEL cases with somewhat
    lower erythroid percentage sharing the same clinicopathologic features are
    still recognized. The diagnosis supersedes AML-MR when its criteria are
    met.
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnostic criteria include erythroid predominance, usually >=80% of
      bone marrow elements, of which >=30% are proerythroblasts (or
      pronormoblasts).
    explanation: WHO-HAEM5 states the defining marrow-percentage criteria for AEL.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The central role that biallelic TP53 mutations play in this aggressive
      AML type is underscored
    explanation: WHO-HAEM5 emphasizes biallelic TP53 alteration as central to the entity.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The diagnosis of AEL supersedes AML-MR.
    explanation: WHO-HAEM5 states the diagnostic precedence of AEL over AML-MR.
- name: ICC AML with mutated TP53 definition (pure erythroid leukemia arm)
  definition_type: DIAGNOSTIC_CRITERIA
  scope: International Consensus Classification 2022
  description: >-
    The ICC does not retain a separately named erythroid-defined entity.
    Instead it folds pure erythroid leukemia into the broader "AML with
    mutated TP53" category, unified by TP53 mutation status rather than
    lineage percentage. This is a materially different classification
    boundary from WHO-HAEM5, not merely a naming difference.
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      By contrast, the 2022 International Consensus Classification (ICC)
      includes PEL under a broader category of "acute myeloid leukemia with
      mutated TP53".
    explanation: >-
      A dedicated PEL case series states the ICC's differing classification
      boundary relative to WHO.
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pure erythroid leukemia (PEL), also known as acute erythroid leukemia
      (AEL), is recognized as a distinct morphologic entity by both the 2016
      and 2022 World Health Organization (WHO) classification system.
    explanation: Confirms WHO's continued recognition of a distinct morphologic entity across editions, contrasted with the ICC's TP53-unified approach.
- name: Retired FAB/WHO 2008-2016 erythroid/myeloid (M6a) category
  definition_type: DIAGNOSTIC_CRITERIA
  scope: Historical FAB and WHO 2001/2008 classification (superseded)
  description: >-
    The FAB classification and WHO 2001/2008 editions recognized two AEL
    subtypes by erythroid/blast percentage alone: "M6a" (erythroid/myeloid,
    >=50% erythroid cells plus >=20% blasts among non-erythroid cells) and
    "M6b" (pure erythroid, >=80% erythroid precursors). WHO 2016 eliminated
    M6a as an AML entity, reclassifying most such cases as MDS, AML-MR, or
    AML/MDS not otherwise specified based on blast percentage rather than
    biology; M6b was retained, renamed pure erythroid leukemia, and is the
    direct ancestor of the current WHO-HAEM5 AEL definition. This history is
    recorded here so the historical FAB "M6" label is not read as
    interchangeable with the current, much narrower AEL concept.
  evidence:
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      "M6a" cases had at least 50% erythroid cells and at least 20% blasts of
      non-erythroid cells in bone marrow.
    explanation: States the historical FAB/WHO 2008 M6a erythroid/myeloid criteria.
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      M6a was merged into a hybrid subtype of myelodysplasia and AML
      (specifically, "myelodysplastic syndrome (MDS) or AML, not otherwise
      specified (NOS) (non-erythroid subtype)" based on the percentage of
      blasts in the bone marrow rather than biological or genetic features.
    explanation: Documents the WHO 2016 reclassification of the erythroid/myeloid category into MDS/AML-NOS by blast percentage.
  - reference: PMID:37246017
    reference_title: "A History and Current Understanding of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Since the first recognition of an erythroid-predominant hematologic
      malignancy in the early 20th century, AEL has gone through a turnstile
      of changing definitions and nomenclature, including eritoleucemia,
      erythremic myelosis, AML-M6 and pure erythroid leukemia.
    explanation: A dedicated history review documents the succession of names and definitions culminating in the current entity.
discussions:
- discussion_id: ael-classification-boundary-controversy
  kind: CONTROVERSY
  prompt: >-
    Should AEL/pure erythroid leukemia be defined by erythroid lineage
    percentage and morphology (the WHO-HAEM5 approach) or unified with other
    TP53-mutated AML/MDS by genomic profile alone (the position argued by
    Iacobucci et al. and reflected in part by the ICC)?
  status: OPEN
  rationale: >-
    A comprehensive genomic comparison of AEL against non-erythroid AML and
    MDS found that the mutational spectrum of AEL is statistically distinct
    from both, arguing against collapsing AEL into either category on
    genomic grounds even though TP53 mutation is common to all three. This
    directly contests the WHO 2016 blast-percentage-driven reclassification
    of the erythroid/myeloid (M6a) category into MDS, and is in tension with
    the ICC's decision to fold pure erythroid leukemia into a TP53-unified
    AML category rather than keep a distinct erythroid entity.
  attaches_to:
  - "pathophysiology#Biallelic TP53 Inactivation"
  evidence:
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, mutational prevalence varies significantly between the three
      major subtypes of myeloid neoplasms (AEL, non-erythroid AML and MDS) in
      both children and adults, suggesting the recent reclassification of
      many AEL case as MDS or AML is unfounded from a mutational perspective.
    explanation: >-
      A large genomic cohort argues the mutational spectrum of AEL is
      distinguishable from MDS and non-erythroid AML, contesting the
      blast-percentage-only rationale for the WHO 2016 reclassification of
      the erythroid/myeloid category. Marked PARTIAL because this is one
      cohort's argument, not a settled resolution, and the current WHO-HAEM5
      and ICC positions differ from it in different directions.
  notes: >-
    Recorded so this entry does not silently pick one classification vintage
    as though the boundary were settled; see the `definitions` block for the
    WHO-HAEM5, ICC, and retired FAB/WHO 2001-2016 positions.
pathophysiology:
- name: Biallelic TP53 Inactivation
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "evading_growth_suppressors#Tumor Suppressor Inactivation"
  description: >-
    Nearly all AEL/pure erythroid leukemia cases carry biallelic TP53
    alteration, most commonly a missense mutation plus deletion or
    copy-neutral loss of heterozygosity of the second allele, or two
    independent clonal TP53 mutations. This is the dominant recurrent lesion
    in the disease and, per WHO-HAEM5, is central to its current diagnostic
    definition.
  genes:
  - preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  gene_products:
  - preferred_term: Cellular Tumor Antigen p53
    term:
      id: NCIT:C17387
      label: Cellular Tumor Antigen p53
  biological_processes:
  - preferred_term: Signal Transduction by p53 Class Mediator
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
    modifier: DECREASED
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cases expressed biallelic TP53 alterations, including TP53
      deletion/single TP53 mutation (68%), two TP53 mutations (29%) or two
      TP53 deletions (3%); additional mutations were infrequent.
    explanation: >-
      A 41-case Mayo Clinic series found universal biallelic TP53 alteration
      in pure erythroid leukemia, with a breakdown of the allelic patterns.
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All but one of the TP53-mutated cases exhibited alterations of both
      alleles, as two clonal sequence mutations (28.0% of mutated cases), a
      mutation and DNA copy-neutral loss of heterozygosity (29.0%), or
      mutation and deletion of the other allele (39%)
    explanation: >-
      An independent genomic cohort corroborates near-universal biallelic
      TP53 alteration among TP53-mutated AEL cases and details the three
      allelic patterns.
  - reference: PMID:35636055
    reference_title: "Differential characteristics of TP53 alterations in pure erythroid leukemia arising after exposure to cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pure erythroid leukemia (PEL) is a rare acute leukemia with a dismal
      prognosis. TP53 mutations are a dominant feature of PEL
    explanation: >-
      A dedicated TP53-in-PEL study states TP53 mutation as the dominant
      genomic feature of the disease.
  - reference: PMID:35636055
    reference_title: "Differential characteristics of TP53 alterations in pure erythroid leukemia arising after exposure to cytotoxic therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The TP53 mutation, commonly missense, was present in the dominant clone in all cases.
    explanation: TP53 mutation is clonally dominant, consistent with it being the founding/driving lesion rather than a subclonal passenger.
  downstream:
  - target: Loss of p53-Dependent Checkpoint and Apoptotic Control
    causal_link_type: DIRECT
    description: >-
      Biallelic loss disables the p53-dependent surveillance that would
      otherwise arrest, senesce, or eliminate cells with damaged or unstable
      genomes.
- name: Loss of p53-Dependent Checkpoint and Apoptotic Control
  biological_scale: CELLULAR
  role: central_effector
  conforms_to: "evading_growth_suppressors#Loss of Cell-Cycle Checkpoint Control"
  description: >-
    With p53 function disabled by biallelic TP53 alteration, the erythroid
    progenitor clone loses the checkpoint and apoptotic responses that would
    normally restrain proliferation of a genomically damaged or unstable
    cell, permitting continued division and accumulation of further genomic
    lesions.
  biological_processes:
  - preferred_term: Negative Regulation of Cell Cycle
    term:
      id: GO:0045786
      label: negative regulation of cell cycle
    modifier: DECREASED
  - preferred_term: Negative Regulation of Apoptotic Process
    term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:36735909
    reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      TP53R248Q does not affect erythroid differentiation but provides
      self-renewal and survival potential, mostly via downregulation of known
      TP53 targets.
    explanation: >-
      A mouse model directly separates the TP53-mutant contribution (survival
      and self-renewal, i.e., checkpoint/apoptosis evasion) from the
      differentiation-arrest contribution of a cooperating lesion.
  downstream:
  - target: Chromothripsis and Complex or Monosomal Karyotype
    causal_link_type: DIRECT
    description: >-
      Loss of p53-dependent genome surveillance permits gross structural
      genomic catastrophes, including chromothripsis, to persist and be
      clonally propagated rather than triggering arrest or death.
- name: Chromothripsis and Complex or Monosomal Karyotype
  biological_scale: MOLECULAR
  role: effector
  conforms_to: "genome_instability_mutation#Mutator Phenotype and Chromosomal Instability"
  description: >-
    AEL/pure erythroid leukemia is characterized by extensive karyotypic
    complexity, including a high rate of chromothripsis (massive, single-event
    chromosome shattering and reassembly) that is significantly enriched in
    TP53-mutated cases relative to MDS and non-erythroid AML. Karyotype is
    complex in essentially all cases and monosomal in the large majority, with
    deletions in 5q and 7q, monosomy 5/7, trisomy 8, and 17p13 abnormalities
    (the region containing TP53 itself) among the most common recurrent
    findings.
  biological_processes:
  - preferred_term: DNA Repair
    term:
      id: GO:0006281
      label: DNA repair
    modifier: DECREASED
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Karyotype was complex in all cases and monosomal in 90%.
    explanation: The Mayo Clinic series reports near-universal complex/monosomal karyotype in pure erythroid leukemia.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the setting of AEL, deletions in 5q and 7q, monosomy 5 and 7, and
      trisomy 8 are the most common abnormalities detected
    explanation: A dedicated AEL review lists the specific recurrent cytogenetic abnormalities within the complex karyotype.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a karyotypic abnormality that may be present on chromosome 17 (17p13)
      has been linked to the p53 loss of function described in a significant
      percentage of AEL patients
    explanation: Directly connects the recurrent 17p13 cytogenetic abnormality to the TP53 loss-of-function driver modeled upstream in this pathograph.
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the presence of chromothripsis, a massive shattering and reassembly of
      chromosomes
    explanation: Defines chromothripsis, the structural-instability phenomenon found recurrently in AEL.
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It was observed only in adults TP53-mutated cases and was associated
      with very poor cytogenetic risk
    explanation: >-
      Chromothripsis in this cohort occurred specifically in TP53-mutated
      adult AEL and tracked with very poor cytogenetic risk, linking the
      trigger lesion to this downstream instability phenotype.
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic alterations of TP53 through sequence or structural
      alterations are a hallmark of a subset of AEL in adults.
    explanation: Directly ties biallelic TP53 alteration to the structural genomic instability phenotype as a hallmark of the disease.
  downstream:
  - target: EPOR/JAK2/STAT5 Signaling Amplification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - focal chromosomal gain/amplification generated by chromosomal instability
    description: >-
      The same structural instability recurrently generates focal
      gains/amplifications of the EPOR and JAK2 loci, disproportionately in
      TP53-mutated, erythroid-predominant (pure erythroid leukemia) cases.
    evidence:
    - reference: PMID:35839275
      reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we found a high frequency of gains and amplifications involving
        EPOR/JAK2 in TP53-mutated cases, particularly those having >80%
        erythroblasts designated as pure erythroid leukemia
      explanation: >-
        A large sequencing cohort links TP53-mutated, structurally unstable
        AEL genomes to recurrent EPOR/JAK2 amplification, especially in the
        pure erythroid (>=80% erythroblast) phenotype.
  - target: Erythroid Maturation Arrest at the Proerythroblast Stage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - cooperating chromatin/transcriptional or signaling lesions generated by
      chromosomal instability, independent of EPOR/JAK2 amplification
    description: >-
      EPOR/JAK2/STAT5 amplification is a proliferative driver in only a
      subset of TP53-mutated AEL; this parallel edge represents the more
      general route by which chromosomal instability's other cooperating
      lesions (e.g., GATA1-complex or epigenetic-regulator dysregulation)
      reach the maturation-arrest node in cases lacking EPOR/JAK2 involvement.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These recent data further highlight the role of DNA methylation in
        AEL molecular biology
      explanation: >-
        Supports a chromosomal-instability-to-maturation-arrest route not
        mediated by EPOR/JAK2 (here, DNA-methylation/epigenetic
        dysregulation); PARTIAL because it evidences one alternative
        cooperating-lesion class rather than establishing the general parallel
        path as a single mechanism.
- name: EPOR/JAK2/STAT5 Signaling Amplification
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    A genetically distinct subset of TP53-mutated AEL, enriched for the pure
    erythroid phenotype, carries focal gains or amplifications of EPOR and/or
    JAK2 (sometimes with activating point mutations in either gene),
    resulting in enhanced STAT5 pathway activation. This erythropoietin-axis
    signaling amplification is a proliferative driver largely specific to
    AEL among TP53-mutated myeloid neoplasms and confers even worse prognosis
    than TP53 mutation alone.
  genes:
  - preferred_term: EPOR
    term:
      id: hgnc:3416
      label: EPOR
  - preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  biological_processes:
  - preferred_term: Erythropoietin-Mediated Signaling Pathway
    term:
      id: GO:0038162
      label: erythropoietin-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:35839275
    reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to activation of the STAT5 pathway, a common feature across
      all AEL cases, these AEL cases exhibited enhanced cell proliferation
      and heme metabolism and often showed high sensitivity to ruxolitinib in
      vitro and in xenograft models, highlighting a potential role of JAK2
      inhibition in therapeutics of AEL.
    explanation: >-
      Directly links EPOR/JAK2 lesions to enhanced STAT5 signaling, cell
      proliferation, and heme-metabolism activity in this subgroup, and to a
      JAK2-inhibitor-sensitive phenotype.
  - reference: PMID:35839275
    reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases were frequently accompanied by gains and amplifications of
      ERG/ETS2 and associated with a very poor prognosis, even compared with
      other TP53-mutated AEL.
    explanation: >-
      Establishes that the EPOR/JAK2-amplified subgroup is a prognostically
      distinct, worse-outcome subset within TP53-mutated AEL.
  downstream:
  - target: Erythroid Maturation Arrest at the Proerythroblast Stage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - enhanced STAT5-driven proliferative signaling in an already
      differentiation-restricted erythroid clone
    description: >-
      Amplified erythropoietin-axis signaling drives proliferation of a
      clonal erythroid population that is concurrently blocked from terminal
      differentiation by cooperating lesions, favoring expansion of arrested
      proerythroblasts rather than mature erythroid progeny.
- name: Erythroid Maturation Arrest at the Proerythroblast Stage
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The defining cellular phenotype of AEL is a block in erythroid
    differentiation at the proerythroblast stage. Mechanistic modeling shows
    that a cooperating lesion (the pediatric NFIA-ETO2 fusion is the best
    characterized example) can impair terminal erythroid differentiation by
    shifting occupancy of erythroid regulatory elements from GATA-motif to
    ETS-motif-containing target genes, repressing the terminal
    differentiation program; this differentiation block cooperates with,
    rather than requires, the TP53-mutant clone's separately conferred
    survival and self-renewal advantage.
  cell_types:
  - preferred_term: proerythroblast
    term:
      id: CL:0000547
      label: proerythroblast
  genes:
  - preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  biological_processes:
  - preferred_term: Erythrocyte Differentiation
    term:
      id: GO:0030218
      label: erythrocyte differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:36735909
    reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      NFIA-ETO2 interferes with erythroid differentiation by preferentially
      binding and repressing erythroid genes that contain NFI binding sites
      and/or are decorated by ETO2, resulting in a activity shift from GATA-
      to ETS-motif-containing target genes.
    explanation: >-
      Direct mechanistic evidence in a mouse erythroblast model for how a
      cooperating fusion lesion produces a differentiation-arrest program
      through transcriptional-motif redistribution away from the erythroid
      GATA program.
  - reference: PMID:36735909
    reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in the presence of 1 of the most prevalent erythroleukemia-associated
      mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant
      clonogenic activity and induced a fully penetrant transplantable
      PEL-like disease in mice.
    explanation: >-
      Shows the maturation-arrest lesion cooperates with mutant TP53 to
      produce a fully penetrant pure-erythroid-leukemia-like disease,
      supporting the causal link modeled here between the two upstream
      pathophysiology arms and this differentiation-arrest node.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent AEL patient transcriptomic data show alterations of transcription
      or downstream signaling factors that mediate GATA1 activity in more
      than 25% of the cases
    explanation: >-
      A dedicated AEL review reports that dysregulation of GATA1 or its
      transcriptional-complex partners is found in over a quarter of cases,
      generalizing the maturation-arrest mechanism beyond the single
      NFIA-ETO2 example.
  downstream:
  - target: Erythroid Dysplasia
    causal_link_type: DIRECT
    description: >-
      Blockade at the proerythroblast stage yields the dysplastic erythroid
      morphology (nuclear budding, multinucleation, megaloblastoid change)
      seen on marrow examination.
  - target: Proerythroblast Accumulation and Marrow Replacement
    causal_link_type: DIRECT
    description: >-
      Cells blocked at the proerythroblast stage cannot exit the
      proliferative compartment through terminal differentiation, so the
      arrested population accumulates in the marrow.
- name: Proerythroblast Accumulation and Marrow Replacement
  biological_scale: TISSUE
  role: effector
  description: >-
    Arrested, immature proerythroblasts progressively expand and replace
    normal trilineage marrow elements, establishing the overt leukemic
    marrow. De novo AEL and AEL arising after MDS or MDS/MPN share this
    prominent proerythroblast-proliferation morphology, and the arrested
    proerythroblast population itself contributes to treatment resistance.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  cell_types:
  - preferred_term: proerythroblast
    term:
      id: CL:0000547
      label: proerythroblast
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Proerythroblast have been shown to play an important role in treatment
      resistance and poor prognosis in AML patients
    explanation: >-
      WHO-HAEM5 states that proerythroblast burden itself contributes to
      treatment resistance and poor prognosis, supporting this node as a
      clinically consequential accumulation rather than a passive
      bystander population.
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PEL was primary in 14 cases, therapy-related in 14, secondary in 12, and undetermined in one.
    explanation: >-
      Documents that this end-stage marrow-replacement phenotype arises
      through multiple clinical routes (de novo, therapy-related, and
      secondary to a prior hematologic disorder), consistent with a shared
      downstream mechanism reached from different upstream contexts.
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      De novo AEL and cases that arise following MDS or MDS/MPN
      share distinctive morphologic features
    explanation: >-
      WHO-HAEM5 states that de novo and secondary AEL share distinctive
      morphologic features; the sentence continues by naming prominent
      proerythroblast proliferation as that feature, correcting a
      previously mis-cited fragment of the same sentence elsewhere in this
      file (the source PDF hyphenates "proerythroblast" across a line break,
      so the quote stops short of that word rather than risk an inexact
      substring match).
  downstream:
  - target: Leukemia
    causal_link_type: DIRECT
    description: >-
      Marrow replacement by a clonal, maturation-arrested erythroid
      population constitutes the overt acute leukemia phenotype.
  - target: Suppression of Normal Hematopoiesis
    causal_link_type: DIRECT
    description: >-
      Expansion of the leukemic proerythroblast compartment crowds out and
      impairs production of normal erythroid, myeloid, and megakaryocytic
      progeny.
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - extramedullary infiltration of the leukemic erythroid clone
    description: >-
      Extramedullary spread of the leukemic proerythroblast population to
      liver and spleen can produce organomegaly.
  - target: Evidence of Hemolysis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - intramedullary destruction of dysplastic, maturation-arrested erythroid
      precursors
    description: >-
      Ineffective erythropoiesis in the dysplastic, arrested erythroid
      compartment produces laboratory evidence of hemolysis.
- name: Suppression of Normal Hematopoiesis
  biological_scale: TISSUE
  role: consequence
  description: >-
    The leukemic marrow environment suppresses normal trilineage
    hematopoiesis, producing the pancytopenia (anemia, thrombocytopenia,
    neutropenia) that dominates the clinical presentation and drives
    infectious and bleeding complications.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  evidence:
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AEL is characterized by proliferation of erythroid and myeloid blast
      cells in the bone marrow and is associated with a poor prognosis
    explanation: >-
      States the marrow-based, proliferative-blast character of AEL that
      underlies subsequent normal-hematopoiesis suppression.
  downstream:
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - suppression of residual normal erythropoiesis by the leukemic clone
    description: Reduced normal erythroid output lowers circulating red-cell mass.
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - suppression of normal megakaryocytic output
    description: Reduced normal megakaryocytic output lowers the platelet count.
  - target: Neutropenia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - suppression of normal granulocytic output
    description: Reduced normal granulocytic output lowers the mature neutrophil count.
histopathology:
- name: Proerythroblast-Predominant Marrow with Marked Dyserythropoiesis
  finding_term:
    preferred_term: Bone marrow dyserythropoiesis with erythroid predominance
    term:
      id: NCIT:C36235
      label: Bone Marrow Dysplasia Present
  diagnostic: true
  description: >-
    Bone marrow shows erythroid predominance (usually >=80% of marrow
    elements) of which >=30% are proerythroblasts/pronormoblasts, with
    marked dyserythropoiesis (nuclear budding, multinucleation, megaloblastoid
    change) that can be difficult to distinguish morphologically from severe
    reactive dyserythropoiesis.
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnostic criteria include erythroid predominance, usually >=80% of
      bone marrow elements, of which >=30% are proerythroblasts (or
      pronormoblasts).
    explanation: WHO-HAEM5 states the diagnostic marrow morphology criteria.
diagnosis:
- name: Bone Marrow Immunophenotyping (CD71-Positive, Myeloid-Marker-Negative Pattern)
  diagnosis_term:
    preferred_term: bone marrow flow cytometry
    term:
      id: NCIT:C38063
      label: Bone Marrow Flow Cytometry
  description: >-
    Immunohistochemistry and flow cytometry characterize the malignant
    erythroid population and exclude a myeloid-lineage blast population.
  markers: >-
    CD71-positive (often overexpressed); may also express Gerbich antigens,
    E-cadherin, carbonic anhydrase 1, CD36, CD68, and dim
    hemoglobin/glycophorin A; myeloperoxidase, HLA-DR, and CD33 typically
    negative in the majority of cells; CD13 and CD117 are variable.
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CD71 is a surface transferrin receptor that is present on most
      erythroid progenitors and is typically overexpressed in AEL blasts and
      erythroid malignant precursors
    explanation: States the CD71-positive marker pattern characterizing the malignant erythroid population.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Myeloperoxidase, HLA-DR, and CD33, which are known markers of myeloid
      lineage, are typically negative in the majority of cells in the
      biopsy
    explanation: States the myeloid-marker-negative pattern that helps exclude a non-erythroid AML immunophenotype.
- name: Bone Marrow Aspirate and Biopsy Morphology
  diagnosis_term:
    preferred_term: bone marrow biopsy
    term:
      id: NCIT:C15193
      label: Bone Marrow Biopsy
  description: >-
    Bone marrow biopsies in AEL are frequently suboptimal (dry tap or
    hemodiluted aspirate), so core biopsy and immunohistochemistry are
    often required alongside aspirate morphology to establish the diagnosis.
  results: Hypercellularity, dyserythropoiesis, and a high percentage of erythroid precursors.
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the most typical features in the bone marrow biopsy are
      hypercellularity, dyserythropoiesis, and a high percentage of erythroid
      precursors
    explanation: States the core morphologic bone-marrow findings used in diagnosis.
phenotypes:
- category: Hematologic
  name: Leukemia
  description: >-
    Clonal proliferation of maturation-arrested leukemic proerythroblasts in
    the bone marrow, with or without circulating blasts.
  phenotype_term:
    preferred_term: Leukemia
    term:
      id: HP:0001909
      label: Leukemia
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute erythroid leukaemia (AEL) (previously pure erythroid leukaemia,
      an acceptable related term in this edition) is a distinct AML type
      characterized by neoplastic proliferation of erythroid cells with
      features of maturation arrest and high prevalence of biallelic TP53
      alterations.
    explanation: WHO-HAEM5 establishes AEL as a distinct AML/leukemia entity.
- category: Hematologic
  name: Erythroid Dysplasia
  description: >-
    Marked dysplastic change in the erythroid lineage, including nuclear
    budding, multinucleation, and megaloblastoid features, is a hallmark
    morphologic finding.
  phenotype_term:
    preferred_term: Erythroid dysplasia
    term:
      id: HP:0031688
      label: Erythroid dysplasia
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the most typical features in the bone marrow biopsy are
      hypercellularity, dyserythropoiesis, and a high percentage of erythroid
      precursors
    explanation: >-
      A dedicated AEL review names dyserythropoiesis directly as one of the
      most typical bone-marrow findings, supporting this phenotype. Replaces
      a previously mis-cited fragment of a WHO-HAEM5 sentence that, in full,
      described proerythroblast proliferation rather than dysplasia.
- category: Hematologic
  name: Anemia
  description: >-
    Suppression of normal erythropoiesis by the leukemic marrow reduces
    circulating red-cell mass.
  frequency: OBLIGATE
  sequelae:
  - target: Pallor
    description: Pallor at diagnosis largely reflects the severity of the underlying anemia.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most prominent symptoms and findings at diagnosis are fever and
      pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and
      evidence of hemolysis
    explanation: >-
      Directly names anemia, with a median hemoglobin figure, as one of the
      most prominent findings at AEL diagnosis.
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 40 patients with an available complete blood cell count presented
      with anemia (100%), essentially all with thrombocytopenia (98%) and
      63% with neutropenia
    explanation: >-
      All 40 evaluable Mayo Clinic patients had anemia (100%), placing it in
      the OBLIGATE band.
- category: Hematologic
  name: Thrombocytopenia
  description: >-
    Marrow replacement suppresses normal megakaryocytic output, reducing the
    platelet count.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 40 patients with an available complete blood cell count presented
      with anemia (100%), essentially all with thrombocytopenia (98%) and
      63% with neutropenia
    explanation: >-
      98% of evaluable Mayo Clinic patients had thrombocytopenia, placing it
      in the VERY_FREQUENT band (80-99%).
- category: Hematologic
  name: Neutropenia
  description: >-
    Marrow replacement suppresses normal granulocytic output, reducing the
    mature neutrophil count and increasing infection risk.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 40 patients with an available complete blood cell count presented
      with anemia (100%), essentially all with thrombocytopenia (98%) and
      63% with neutropenia
    explanation: >-
      63% of evaluable Mayo Clinic patients had neutropenia, placing it in
      the FREQUENT band (30-79%).
- category: Constitutional
  name: Fever
  description: >-
    Fever is one of the most prominent presenting findings in AEL, alongside
    pallor, anemia, hepatosplenomegaly, and evidence of hemolysis.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most prominent symptoms and findings at diagnosis are fever and
      pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and
      evidence of hemolysis
    explanation: Names fever as one of the most prominent findings at AEL diagnosis.
- category: Constitutional
  name: Pallor
  description: >-
    Pallor at diagnosis largely reflects the severity of the underlying
    anemia.
  phenotype_term:
    preferred_term: Pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most prominent symptoms and findings at diagnosis are fever and
      pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and
      evidence of hemolysis
    explanation: Names pallor as one of the most prominent findings at AEL diagnosis.
- category: Constitutional
  name: Hepatosplenomegaly
  description: >-
    Hepatosplenomegaly, reflecting extramedullary erythroid/leukemic
    infiltration, is reported among the most prominent findings at diagnosis.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most prominent symptoms and findings at diagnosis are fever and
      pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and
      evidence of hemolysis
    explanation: Names hepatosplenomegaly as one of the most prominent findings at AEL diagnosis.
- category: Hematologic
  name: Evidence of Hemolysis
  description: >-
    Laboratory evidence of hemolysis (e.g., elevated bilirubin/LDH, reduced
    haptoglobin) is reported among the most prominent findings at diagnosis,
    alongside the leukemic marrow's ineffective erythropoiesis.
  phenotype_term:
    preferred_term: Evidence of hemolysis
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the most prominent symptoms and findings at diagnosis are fever and
      pallor, anemia (median hemoglobin of 7.5 g/L), hepatosplenomegaly, and
      evidence of hemolysis
    explanation: Names evidence of hemolysis as one of the most prominent findings at AEL diagnosis.
  notes: >-
    HP:0001878 (Hemolytic anemia) is the closest available term but is
    slightly stronger than the source's "evidence of hemolysis" (e.g.
    elevated bilirubin/LDH, reduced haptoglobin), which does not itself
    assert a diagnosis of hemolytic anemia.
genetic:
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Central, near-universal somatic driver lesion; biallelic alteration is characteristic of the disease
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  variants:
  - name: Biallelic TP53 alteration (mutation plus deletion/LOH, or two mutations)
    description: >-
      Biallelic TP53 alteration occurs through one of three patterns: a
      single missense/nonsense mutation combined with deletion of the other
      allele, a single mutation combined with copy-neutral loss of
      heterozygosity, or two independent clonal mutations. Missense
      mutations predominate and are most often in the DNA-binding domain.
    gene:
      preferred_term: TP53
      term:
        id: hgnc:11998
        label: TP53
    type: biallelic_alteration
    functional_effects:
    - function: p53-dependent checkpoint and apoptotic signaling
      description: >-
        Biallelic loss-of-function alteration abolishes p53-dependent
        surveillance of genomic damage.
      type: loss of function
    evidence:
    - reference: PMID:30926971
      reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All but one of the TP53-mutated cases exhibited alterations of both
        alleles, as two clonal sequence mutations (28.0% of mutated cases), a
        mutation and DNA copy-neutral loss of heterozygosity (29.0%), or
        mutation and deletion of the other allele (39%)
      explanation: Establishes the three recurrent biallelic-alteration patterns and their relative frequency.
  case_fractions:
  - population: Mayo Clinic pure erythroid leukemia case series
    case_fraction_percent: 100.0
    cohort_size: 41
    notes: >-
      All 41 cases in this series carried biallelic TP53 alteration; this is
      a case-series fraction among patients already diagnosed with pure
      erythroid leukemia, not a general-population or all-AML frequency.
    evidence:
    - reference: PMID:36323674
      reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All cases expressed biallelic TP53 alterations, including TP53
        deletion/single TP53 mutation (68%), two TP53 mutations (29%) or two
        TP53 deletions (3%); additional mutations were infrequent.
      explanation: States the 100% biallelic TP53 alteration rate in this cohort with the allelic-pattern breakdown.
  review_notes: >-
    TP53 alteration in this disease is essentially always biallelic; a
    single heterozygous TP53 mutation without a second hit is atypical for
    AEL/pure erythroid leukemia as currently defined and should prompt
    reconsideration of the diagnosis or search for a cryptic second hit
    (structural variation, LOH).
- name: EPOR
  gene_term:
    preferred_term: EPOR
    term:
      id: hgnc:3416
      label: EPOR
  association: Recurrent focal amplification defining a poor-prognosis, pure-erythroid-phenotype subset of TP53-mutated AEL
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:35839275
    reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found a high frequency of gains and amplifications involving
      EPOR/JAK2 in TP53-mutated cases, particularly those having >80%
      erythroblasts designated as pure erythroid leukemia
    explanation: Establishes EPOR amplification as a recurrent cooperating lesion enriched in the pure-erythroid, TP53-mutated subgroup.
  review_notes: >-
    EPOR/JAK2 co-amplification defines a subgroup with in vitro and xenograft
    sensitivity to the JAK inhibitor ruxolitinib; this is preclinical model
    evidence, not an established clinical treatment indication.
- name: JAK2
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  association: Recurrent focal amplification, and occasional activating mutation, cooperating with TP53 loss and EPOR amplification
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:35839275
    reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases were frequently accompanied by gains and amplifications of
      ERG/ETS2 and associated with a very poor prognosis, even compared with
      other TP53-mutated AEL.
    explanation: Establishes the JAK2/EPOR-amplified subgroup as prognostically distinct within TP53-mutated AEL.
- name: GATA1
  gene_term:
    preferred_term: GATA1
    term:
      id: hgnc:4170
      label: GATA1
  association: Recurrent dysregulation of the GATA1 transcriptional complex, either directly or via its interacting partners, underlying the erythroid maturation arrest
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  case_fractions:
  - population: AEL patient transcriptomic cohorts
    case_fraction_percent: 25.0
    notes: >-
      "More than 25%" is a lower-bound estimate reported by a review
      synthesizing transcriptomic data across AEL cohorts; it captures
      dysregulation of GATA1 activity itself or of its direct transcriptional
      partners/interactors (e.g., ERG, ETO2, SKI, SPI1), not GATA1 coding
      mutation alone.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Recent AEL patient transcriptomic data show alterations of
        transcription or downstream signaling factors that mediate GATA1
        activity in more than 25% of the cases
      explanation: States the case fraction with dysregulated GATA1-complex activity.
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ectopic expression of these physical or functional interactors of the
      GATA1 transcriptional complexes (ERG, ETO2, SKI, and SPI1) in murine
      erythroid progenitors resulted in decreased chromatin accessibility at
      GATA1-binding sites and promoted proliferation with the immature
      phenotype
    explanation: >-
      A review of mouse-model data shows that ectopic expression of GATA1
      transcriptional-complex interactors reduces accessibility at
      GATA1-binding sites and drives an immature, proliferative erythroid
      phenotype, mechanistically supporting GATA1-complex disruption as a
      route to the maturation-arrest node.
  - reference: DOI:10.1097/hs9.0000000000000558
    reference_title: "Molecular Landscapes and Models of Acute Erythroleukemia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the pathogenesis of the disease is based on the interplay between
      signaling mutations, impaired TP53 function, and altered chromatin
      organization. These alterations lead to aberrant activity of erythroid
      transcriptional master regulators like GATA1
    explanation: >-
      A dedicated review of AEL molecular models synthesizes human genetics
      and mouse-model data to the same conclusion: signaling mutations,
      impaired TP53 function, and chromatin dysregulation converge on
      aberrant GATA1 activity.
  review_notes: >-
    GATA1 itself is only rarely directly mutated or fused (e.g., MYB-GATA1)
    in AEL; the more common route to erythroid maturation arrest is
    dysregulation of its transcriptional-complex partners (ERG, ETO2, SKI,
    SPI1, FLI1) rather than a GATA1 coding lesion, per the same review.
- name: TET2
  gene_term:
    preferred_term: TET2
    term:
      id: hgnc:25941
      label: TET2
  association: Recurrent cooperating epigenetic-regulator mutation
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  case_fractions:
  - population: Mayo Clinic pure erythroid leukemia case series (updated AEL definitions)
    case_fraction_percent: 20.0
    cohort_size: 41
    notes: Modern (2016-2022 definition), TP53-biallelic-restricted AEL cohort.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The recent analysis of 41 AEL patients by the Mayo Clinic with the
        updated AEL definitions demonstrated that 20% of patients had
        mutations in TET2 and 10% of patients had mutations in ASXL1, IDH2,
        and DNMT3A.
      explanation: States the TET2 co-mutation fraction in a modern-definition AEL cohort.
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA methylation plays an essential role in erythroid malignancies, and
      it is regulated by several factors, including TET2 and DNMT3A/B
    explanation: Establishes TET2's mechanistic role in the DNA-methylation dysregulation implicated in AEL.
- name: ASXL1
  gene_term:
    preferred_term: ASXL1
    term:
      id: hgnc:18318
      label: ASXL1
  association: Recurrent cooperating epigenetic-regulator mutation
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  case_fractions:
  - population: Mayo Clinic pure erythroid leukemia case series (updated AEL definitions)
    case_fraction_percent: 10.0
    cohort_size: 41
    notes: Modern (2016-2022 definition), TP53-biallelic-restricted AEL cohort.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The recent analysis of 41 AEL patients by the Mayo Clinic with the
        updated AEL definitions demonstrated that 20% of patients had
        mutations in TET2 and 10% of patients had mutations in ASXL1, IDH2,
        and DNMT3A.
      explanation: States the ASXL1 co-mutation fraction in a modern-definition AEL cohort.
- name: IDH2
  gene_term:
    preferred_term: IDH2
    term:
      id: hgnc:5383
      label: IDH2
  association: Recurrent cooperating epigenetic-regulator mutation
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  case_fractions:
  - population: Mayo Clinic pure erythroid leukemia case series (updated AEL definitions)
    case_fraction_percent: 10.0
    cohort_size: 41
    notes: Modern (2016-2022 definition), TP53-biallelic-restricted AEL cohort.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The recent analysis of 41 AEL patients by the Mayo Clinic with the
        updated AEL definitions demonstrated that 20% of patients had
        mutations in TET2 and 10% of patients had mutations in ASXL1, IDH2,
        and DNMT3A.
      explanation: States the IDH2 co-mutation fraction in a modern-definition AEL cohort.
- name: DNMT3A
  gene_term:
    preferred_term: DNMT3A
    term:
      id: hgnc:2978
      label: DNMT3A
  association: Recurrent cooperating epigenetic-regulator mutation
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  case_fractions:
  - population: Mayo Clinic pure erythroid leukemia case series (updated AEL definitions)
    case_fraction_percent: 10.0
    cohort_size: 41
    notes: Modern (2016-2022 definition), TP53-biallelic-restricted AEL cohort.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The recent analysis of 41 AEL patients by the Mayo Clinic with the
        updated AEL definitions demonstrated that 20% of patients had
        mutations in TET2 and 10% of patients had mutations in ASXL1, IDH2,
        and DNMT3A.
      explanation: States the DNMT3A co-mutation fraction in a modern-definition AEL cohort.
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA methylation plays an essential role in erythroid malignancies, and
      it is regulated by several factors, including TET2 and DNMT3A/B
    explanation: Establishes DNMT3A's mechanistic role in the DNA-methylation dysregulation implicated in AEL.
- name: BCOR
  gene_term:
    preferred_term: BCOR
    term:
      id: hgnc:20893
      label: BCOR
  association: Recurrent cooperating epigenetic-regulator mutation linked to treatment resistance
  relationship_type: COOPERATING
  variant_origin: SOMATIC
  evidence:
  - reference: PMID:35015684
    reference_title: "BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      highly recurrent mutations of the PRC1 subunits BCOR and BCORL1 in
      leukemia disrupt assembly of a noncanonical PRC1.1 complex, thereby
      selectively unlinking the RING-PCGF enzymatic core from the
      chromatin-targeting auxiliary subcomplex
    explanation: >-
      Establishes the mechanistic consequence of BCOR mutation (loss of
      PRC1.1 repressive function) in leukemia cell-line and patient-sample
      systems.
  - reference: PMID:35015684
    reference_title: "BCOR and BCORL1 Mutations Drive Epigenetic Reprogramming and Oncogenic Signaling by Unlinking PRC1.1 from Target Genes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      BCOR-mutated PRC1.1 is localized to chromatin but lacks repressive
      activity, leading to epigenetic reprogramming and transcriptional
      activation at target loci
    explanation: >-
      States the specific epigenetic-reprogramming mechanism by which BCOR
      mutation drives aberrant transcription.
  review_notes: >-
    This mechanism was characterized in leukemia broadly (including
    BCOR-mutated myeloid neoplasms and cell-line/patient-sample systems), not
    specifically in AEL; it is included here because BCOR/BCORL1 mutation
    with or without DNMT3A co-mutation has been reported as a cooperating
    lesion with TP53 loss and NFIA-ETO2 in AEL mouse models (see
    `animal_models`).
animal_models:
- name: NFIA-ETO2 fusion with cooperating TP53 R248Q (murine erythroblast transplant model)
  species: Mouse
  genotype: >-
    t(1;16)(p31;q24) NFIA-ETO2 fusion expressed in murine erythroleukemia
    cells and primary fetal-liver-derived erythroblasts, with or without
    cooperating Trp53 R248Q
  publication: PMID:36735909
  modeled_mechanisms:
  - target: Erythroid Maturation Arrest at the Proerythroblast Stage
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      NFIA-ETO2 expression increases proliferation and impairs erythroid
      differentiation, shifting transcription-factor occupancy from
      GATA-motif to ETS-motif target genes, recapitulating the
      GATA1-complex-based maturation-arrest mechanism modeled at this node.
    limitations: >-
      The t(1;16)(p31;q24) NFIA-ETO2 fusion has so far been reported
      exclusively in pediatric pure erythroid leukemia, so this model
      specifically supports the maturation-arrest mechanism in that rare
      genetic subgroup, not the TP53-driven adult-onset disease that
      dominates AEL case series.
    readouts:
    - name: Erythroid differentiation and proliferation of NFIA-ETO2-expressing erythroblasts
      target: Erythroid Maturation Arrest at the Proerythroblast Stage
      direction: DECREASED
      interpretation: Direct measurement of impaired terminal erythroid differentiation caused by the fusion.
      evidence:
      - reference: PMID:36735909
        reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          NFIA-ETO2 significantly increased proliferation and impaired
          erythroid differentiation of murine erythroleukemia cells and of
          primary fetal liver-derived EBs.
        explanation: Direct readout of the differentiation-arrest phenotype in the mouse model.
    evidence:
    - reference: PMID:36735909
      reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        NFIA-ETO2 interferes with erythroid differentiation by preferentially
        binding and repressing erythroid genes that contain NFI binding
        sites and/or are decorated by ETO2, resulting in a activity shift
        from GATA- to ETS-motif-containing target genes.
      explanation: Establishes the model as informative for the GATA-to-ETS transcriptional mechanism modeled at this node.
  - target: Loss of p53-Dependent Checkpoint and Apoptotic Control
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Adding TP53 R248Q to NFIA-ETO2-expressing erythroblasts converts a
      non-transplantable cell population into a fully penetrant,
      transplantable pure-erythroid-leukemia-like disease; TP53 R248Q itself
      does not alter erythroid differentiation but instead confers
      self-renewal and survival via downregulation of TP53 target genes,
      directly recapitulating the checkpoint/apoptosis-evasion role modeled
      at this node.
    limitations: >-
      A single hotspot TP53 allele (R248Q) was used; whether every biallelic
      TP53 alteration pattern seen in human AEL confers an equivalent
      self-renewal advantage in this system was not tested.
    readouts:
    - name: Clonogenic activity and transplantability of NFIA-ETO2 plus TP53 R248Q erythroblasts
      target: Loss of p53-Dependent Checkpoint and Apoptotic Control
      direction: INCREASED
      interpretation: >-
        TP53 R248Q converts the fusion-alone phenotype into a transplantable
        leukemia, evidencing a survival/self-renewal gain rather than a
        differentiation effect.
      evidence:
      - reference: PMID:36735909
        reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          in the presence of 1 of the most prevalent erythroleukemia-associated
          mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant
          clonogenic activity and induced a fully penetrant transplantable
          PEL-like disease in mice.
        explanation: Direct readout of transplantable-leukemia induction attributable to the TP53 mutation.
    evidence:
    - reference: PMID:36735909
      reference_title: "The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        TP53R248Q does not affect erythroid differentiation but provides
        self-renewal and survival potential, mostly via downregulation of
        known TP53 targets.
      explanation: Directly separates the TP53-mutant contribution (checkpoint/apoptosis evasion) from the differentiation-arrest contribution of NFIA-ETO2.
- name: CRISPR/Cas9 Trp53 plus Bcor mutant hematopoietic stem/progenitor cell mouse model
  species: Mouse
  genotype: CRISPR/Cas9-induced Trp53 and Bcor mutations in hematopoietic stem/progenitor cells
  publication: PMID:38892446
  modeled_mechanisms:
  - target: Erythroid Maturation Arrest at the Proerythroblast Stage
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Combining Trp53 and Bcor mutations in mouse HSPCs by CRISPR/Cas9
      produces AEL-like tumors with a gene-expression profile recapitulating
      human AEL, including overexpression of the erythroid transcription
      factors Gata1, Gata2, and Klf1, directly supporting the GATA-complex
      dysregulation mechanism modeled at this node and linking it to the
      BCOR cooperating lesion.
    limitations: >-
      Reported here via a secondary review description rather than the
      primary study, so experimental detail (penetrance, latency, additional
      cooperating events) cannot be independently verified in this entry.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mouse AEL tumors established by CRISPR/Cas9 of HSPCs with Trp53 and
        Bcor mutations had a gene expression profile recapitulating human
        AEL tumors with an overexpression of erythroid transcription factors
        such as Gata1, Gata2, and Klf1
      explanation: >-
        A review reports this mouse-model finding; marked PARTIAL because
        the review is a secondary source for the primary experimental result.
- name: ERG-transduced TP53-mutant hematopoietic stem/progenitor cell transplant model
  species: Mouse
  genotype: Retroviral ERG overexpression in TP53-mutated hematopoietic stem/progenitor cells
  publication: PMID:38892446
  modeled_mechanisms:
  - target: EPOR/JAK2/STAT5 Signaling Amplification
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Transplanting purified ERG-transduced TP53-mutated hematopoietic
      stem/progenitor-cell-derived erythroblasts produces fatal
      erythroleukemia within about 60 days, showing that ERG upregulation -
      the same ERG/ETS2 locus recurrently co-amplified with EPOR/JAK2 in
      human AEL - cooperates with TP53 mutation to drive erythroid
      leukemogenesis.
    limitations: >-
      This model tests retroviral ERG overexpression alone, not the focal
      EPOR/JAK2/ERG co-amplification event seen in human AEL, and evidence
      is drawn from a secondary review description rather than the primary
      study, so mechanistic detail (dose, kinetics, STAT5 pathway
      involvement specifically) cannot be independently verified here.
    evidence:
    - reference: PMID:38892446
      reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        transplanting purified ERG-transduced TP53-mutated HSPC erythroblasts
        resulted in fatal erythroleukemia within 60 days
      explanation: >-
        A review reports this mouse transplant finding; marked PARTIAL
        because the review is a secondary source for the primary
        experimental result and does not report STAT5 pathway activation
        specifically for this model.
differential_diagnoses:
- name: Erythroid Hyperplasia in Megaloblastic Anemia
  disease_term:
    preferred_term: megaloblastic anemia
    term:
      id: MONDO:0001700
      label: megaloblastic anemia
  description: >-
    Severe vitamin B12 or folate deficiency produces marked erythroid
    hyperplasia with megaloblastic, sometimes strikingly atypical, erythroid
    precursors that can superficially resemble the dysplastic proerythroblast
    proliferation of AEL. Unlike AEL, this is a reactive, non-clonal process
    driven by ineffective erythropoiesis and intramedullary destruction of
    defective erythroid precursors, and it resolves with B12/folate
    repletion rather than requiring leukemia-directed therapy.
  distinguishing_features:
  - >-
    Megaloblastic marrow lacks biallelic TP53 alteration and complex/monosomal
    karyotype, unlike AEL/pure erythroid leukemia.
  - >-
    Erythroid precursors show classic megaloblastic nuclear-cytoplasmic
    asynchrony rather than the proerythroblast-predominant dysplasia of AEL.
  - >-
    Low serum B12/folate, elevated methylmalonic acid and/or homocysteine,
    and rapid, complete hematologic resolution with vitamin repletion confirm
    the diagnosis.
  evidence:
  - reference: PMID:19094231
    reference_title: "Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concurrent hemolysis in patients with vitamin B12 deficiency is a
      well-recognized phenomenon and has been attributed to intramedullary
      destruction of erythrocytes (ineffective erythropoiesis).
    explanation: >-
      Supports the reactive, ineffective-erythropoiesis basis of the
      erythroid hyperplasia seen in B12 deficiency, distinguishing its
      mechanism from the clonal, TP53-driven proliferation of AEL.
- name: Congenital Dyserythropoietic Anemia
  disease_term:
    preferred_term: congenital dyserythropoietic anemia
    term:
      id: MONDO:0019403
      label: congenital dyserythropoietic anemia
  description: >-
    The congenital dyserythropoietic anemias (CDAs) are inherited disorders
    of erythroid differentiation/proliferation that produce dysplastic
    erythroid precursors (multinuclearity, internuclear chromatin bridging)
    and ineffective erythropoiesis, morphologically overlapping with the
    dyserythropoiesis of AEL but arising from germline variants rather than
    an acquired, TP53-driven clonal leukemic process.
  distinguishing_features:
  - >-
    CDA presents from infancy/childhood with a chronic, non-progressive
    course and a specific germline genetic cause (e.g., CDAN1, SEC23B, KLF1),
    without biallelic TP53 alteration, complex karyotype, or blast excess.
  - >-
    CDA shows characteristic ultrastructural findings (e.g., binuclearity,
    chromatin bridges, or a spongy heterochromatin pattern depending on
    type), whereas AEL shows leukemic proerythroblast-predominant dysplasia.
  - >-
    AEL is acquired, typically presents in older adults, and carries the
    TP53/cytogenetic abnormalities characteristic of clonal leukemia.
  evidence:
  - reference: PMID:32702750
    reference_title: "Congenital dyserythropoietic anemias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group
      of inherited anemias that affect the normal differentiation-proliferation
      pathways of the erythroid lineage.
    explanation: Defines CDA as an inherited erythroid differentiation disorder, the key distinction from acquired, clonal AEL.
  - reference: PMID:32702750
    reference_title: "Congenital dyserythropoietic anemias."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      They belong to the wide group of ineffective erythropoiesis conditions
      that mainly result in monolinear cytopenia.
    explanation: Characterizes CDA as an ineffective-erythropoiesis, monolinear-cytopenia disorder rather than a leukemic marrow-replacement process.
- name: Myelodysplastic Syndrome with Erythroid Predominance
  disease_term:
    preferred_term: myelodysplastic syndrome
    term:
      id: MONDO:0018881
      label: myelodysplastic syndrome
  description: >-
    Myelodysplastic syndrome can present with marked erythroid hyperplasia
    and dysplasia, and this is precisely the diagnostic space the retired
    "erythroid/myeloid" (M6a) AEL category was reclassified into under WHO
    2016: cases with erythroid predominance but blast counts and biology
    below the current AEL threshold are now diagnosed as MDS rather than AEL.
  distinguishing_features:
  - >-
    Diagnosis turns on the current WHO-HAEM5 blast/proerythroblast thresholds
    (AEL requires marked erythroid predominance with >=30% proerythroblasts).
  - >-
    Biallelic TP53 alteration with complex/monosomal karyotype favors
    AEL/pure erythroid leukemia, while lower blast counts, non-TP53
    MDS-typical mutations (e.g., SF3B1, ASXL1), and a more indolent course
    favor MDS.
  - >-
    The ICC's TP53-unified "AML with mutated TP53" category and the ongoing
    genomic-versus-morphologic classification debate (see `discussions`)
    mean this boundary is actively contested rather than fixed.
  evidence:
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      M6a was merged into a hybrid subtype of myelodysplasia and AML
      (specifically, "myelodysplastic syndrome (MDS) or AML, not otherwise
      specified (NOS) (non-erythroid subtype)" based on the percentage of
      blasts in the bone marrow rather than biological or genetic features.
    explanation: >-
      Documents the specific reclassification of erythroid-predominant,
      lower-blast cases into MDS/AML-NOS; this is a classification-history
      statement rather than a primary clinical-cohort finding, so
      evidence_source is OTHER (matching the other citation of this same
      sentence elsewhere in this file).
  - reference: PMID:30926971
    reference_title: "Genomic subtyping and therapeutic targeting of acute erythroleukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MDS-associated mutations such as SF3B1 and
      ASXL1 were less frequent in AEL compared to MDS
    explanation: Provides a molecular distinguishing feature (relative depletion of classic MDS-driver mutations in AEL) supporting differentiation from MDS.
treatments:
- name: Hypomethylating Agent Plus Venetoclax
  description: >-
    Combination therapy with a hypomethylating agent (azacitidine or
    decitabine) and the BCL-2 inhibitor venetoclax is the most commonly used
    regimen in reported AEL/pure erythroid leukemia series, reflecting its
    broader use in TP53-mutated and older/unfit AML. Reported outcomes remain
    poor: in one series no responses or allogeneic transplants were achieved
    regardless of regimen.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azacitidine
      term:
        id: CHEBI:2038
        label: 5-azacytidine
    - preferred_term: venetoclax
      term:
        id: CHEBI:133021
        label: venetoclax
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment details were available in 29 patients: hypomethylating agent
      (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy
      (n = 4), supportive care/other (n = 8)
    explanation: Documents HMA + venetoclax as the most frequently used regimen among treated patients in this series.
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no responses or allogeneic stem cell transplants were documented, and
      all patients died at a median 1.8 months (range 0.2-9.3).
    explanation: >-
      Reports the outcome across all treatment approaches in this series,
      establishing that current regimens are largely ineffective rather than
      overstating any single regimen's benefit.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      erythroid/megakaryocytic AML subtypes are associated with resistance to
      venetoclax
    explanation: States the specific venetoclax-resistance association in erythroid/megakaryocytic AML subtypes such as AEL.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AML cells exhibiting erythroid/megakaryocytic differentiation depend on
      BCL-XL rather than BCL-2 for their survival
    explanation: >-
      States the underlying mechanistic finding (BCL-XL rather than BCL-2
      dependence) that explains the venetoclax-resistance association.
- name: Intensive Cytarabine-Based Chemotherapy
  description: >-
    Intensive induction chemotherapy analogous to standard AML regimens is
    used in a minority of patients, generally younger or fitter ones, but
    has not been shown to produce durable responses in reported AEL/pure
    erythroid leukemia series.
  treatment_term:
    preferred_term: Chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: cytarabine
      term:
        id: CHEBI:28680
        label: cytarabine
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment details were available in 29 patients: hypomethylating agent
      (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy
      (n = 4), supportive care/other (n = 8)
    explanation: Documents intensive chemotherapy as one of the treatment approaches used, though in a minority of patients.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The objective response rate (ORR) was 72%, according to the ELN
      criteria. Complete response (CR) occurred in 79 patients (66%), partial
      response (PR) in 7 (6%), stable disease (SD) in 16 (13%), and primary
      disease progression (PPD) in 17 (14%).
    explanation: >-
      A 217-patient multinational cohort reports substantial response rates
      to intensive chemotherapy; marked PARTIAL because this cohort applied
      older, less stringent AEL definitions and so overlaps what would now be
      classified as MDS or other AML, per the same review.
- name: Allogeneic Hematopoietic Cell Transplantation
  description: >-
    Allogeneic hematopoietic cell transplantation (allo-HCT), typically as
    consolidation after remission induction, is the only treatment approach
    reported to be potentially curative in AEL/pure erythroid leukemia.
    Achieving the deep remission required to proceed to transplant is itself
    a major challenge in this TP53-driven, chemoresistant disease, so only a
    minority of patients reach transplant.
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  evidence:
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allogeneic bone marrow transplantation (AlloBMT) is the only
      potentially curative approach for AEL, but it requires deep remission
      of the disease, which is rarely achieved in these patients
    explanation: States that allo-HCT is the only potentially curative approach, and names the deep-remission requirement that limits how many patients reach it.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median OS of AlloBMT recipients was 89 months, compared to 5 months
      for those who did not undergo AlloBMT
    explanation: >-
      Reports a large survival benefit for patients who reach transplant
      versus those who do not, in a cohort study cited by this review; this
      is a selected-population comparison (transplant eligibility itself
      correlates with fitness and remission depth) rather than a randomized
      estimate of transplant's isolated effect. The cohort also used the
      2008 WHO classification of AEL, broader than the current WHO-HAEM5
      definition used in this entry, so the magnitude should not be assumed
      to transfer unchanged to TP53-biallelic-restricted modern AEL.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the definition of AEL for this analysis was based on the 2008 WHO
      classification
    explanation: >-
      States the classification-vintage caveat directly; marked PARTIAL
      because it qualifies rather than supports the 89-vs-5-month claim on
      its own.
- name: Investigational JAK Inhibition in EPOR/JAK2-Amplified Disease
  description: >-
    In preclinical models, AEL cases with EPOR and/or JAK2 gain/amplification
    show high sensitivity to the JAK1/2 inhibitor ruxolitinib in vitro and in
    patient-derived xenografts, suggesting a targeted therapeutic strategy
    for this molecularly defined subgroup. This is model-system evidence and
    has not been established as a standard clinical treatment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: EPOR/JAK2/STAT5 Signaling Amplification
    treatment_effect: INHIBITS
    description: >-
      Ruxolitinib inhibits JAK1/2 kinase activity, blocking the amplified
      EPOR/JAK2-driven STAT5 signaling that this subgroup depends on.
  evidence:
  - reference: PMID:35839275
    reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Their frequent response to ruxolitinib in patient-derived xenograft and
      cell culture models highlights a possible therapeutic role of JAK2
      inhibition for erythroleukemia with EPOR/JAK2-involving lesions.
    explanation: >-
      States the preclinical (patient-derived xenograft and cell culture)
      basis for JAK2 inhibition as a possible targeted approach in this
      genomically defined subgroup; evidence_source is MODEL_ORGANISM because
      the response data are from xenograft and cell-line models, not treated
      patients.
- name: Best Supportive Care
  description: >-
    Given the dismal response to available regimens, many patients,
    particularly those unfit for intensive or hypomethylating-agent-based
    therapy, are managed with supportive care (transfusion support,
    infection prophylaxis/treatment) alone.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment details were available in 29 patients: hypomethylating agent
      (HMA) alone (n = 5), HMA + venetoclax (n = 12), intensive chemotherapy
      (n = 4), supportive care/other (n = 8)
    explanation: Documents supportive care/other as a treatment approach used in nearly a third of treated patients in this series.
clinical_trials:
- name: NCT02861651
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Observational molecular-characterization study using array comparative
    genomic hybridization and targeted next-generation sequencing of 106
    myeloid/erythrocyte-differentiation genes in 40 cases of the older,
    broader erythroid/myeloid (M6a) AEL subtype, aiming to determine whether
    M6a-AML constitutes a distinct AML class and to document the basis for
    its poor prognosis. Predates WHO-HAEM5 and does not target the
    TP53-biallelic, pure-erythroid-restricted entity scoped by this file.
  evidence:
  - reference: clinicaltrials:NCT02861651
    reference_title: "Molecular Characterization of Acute Erythroid Leukemia (M6-AML) Using Targeted Next-generation Sequencing"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the investigators will search for molecular alterations in 40 M6a-AMLs
      using array comparative genomic hybridization (aCGH) and
      next-generation sequencing (NGS) of 106 genes known or suspected to
      have a role in myeloid malignancies or in erythrocyte differentiation.
    explanation: >-
      States the trial's molecular-characterization objective and design;
      observational, so evidence_source is OTHER rather than a
      treatment-outcome classification.
prevalence:
- population: Reported AML case series (AEL as a proportion of all AML)
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    AEL/pure erythroid leukemia accounts for approximately 0.5% to 1.5% of
    all AML cases in reported series; this is a proportion of diagnosed AML,
    not a general-population prevalence rate, so no rate_per_100000 is given.
    Reported cohorts have a median diagnosis age of approximately 67 years
    (with some evidence of a bimodal distribution, a smaller peak around age
    20) and a male-to-female ratio of approximately 2.4:1.
  evidence:
  - reference: PMID:35839275
    reference_title: "Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      acute erythroid leukemia (AEL) represents a rare subtype of acute
      myeloid leukemia (AML), accounting for 0.5% to 1.5% of AML cases
    explanation: States the proportion of AML cases represented by AEL.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median age of AEL diagnosis is 67 years old, though some studies
      have demonstrated a bimodal age of diagnosis with a small peak at
      around 20 years old and a larger second peak in the early 70s.
    explanation: States the median diagnosis age and bimodal age distribution.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This disease also demonstrates a slight male-to-female predominance
      (2.4:1)
    explanation: States the male-to-female sex ratio.
progression:
- phase: Diagnosis and TP53/Cytogenetic Risk Assessment
  notes: >-
    Diagnosis requires marrow morphology meeting the current WHO-HAEM5
    erythroid-predominance/proerythroblast threshold plus TP53 mutation
    testing and karyotype, since biallelic TP53 alteration and
    complex/monosomal karyotype are near-universal and central to both
    diagnosis and prognosis. EPOR/JAK2 status may further stratify a
    molecularly distinct, especially poor-prognosis subgroup.
  evidence:
  - reference: PMID:35732831
    reference_title: "The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The central role that biallelic TP53 mutations play in this aggressive
      AML type is underscored
    explanation: WHO-HAEM5 places TP53 status at the center of the diagnostic and prognostic framework for this disease.
- phase: Rapid Clinical Decline Despite Treatment
  notes: >-
    Reported outcomes are extremely poor overall. A 41-case, entirely
    TP53-biallelic Mayo Clinic series treated across the modern HMA/HMA
    plus venetoclax/intensive-chemotherapy/supportive-care spectrum saw no
    responses or transplants and a median survival of 1.8 months. A larger,
    more heterogeneous 217-patient multinational cohort using older
    definitions reported a longer median overall survival, and the small
    subset of patients who reached allogeneic transplant fared
    substantially better than those who did not (see the Allogeneic
    Hematopoietic Cell Transplantation treatment entry) - underscoring that
    reaching deep remission and transplant, not any single drug regimen, is
    the main outcome-modifying factor identified so far.
  evidence:
  - reference: PMID:36323674
    reference_title: "Pure (acute) erythroid leukemia: morphology, immunophenotype, cytogenetics, mutations, treatment details, and survival data among 41 Mayo Clinic cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no responses or allogeneic stem cell transplants were documented, and
      all patients died at a median 1.8 months (range 0.2-9.3).
    explanation: Documents the extremely poor outcome across treatment approaches in this series.
  - reference: PMID:37246017
    reference_title: "A History and Current Understanding of Acute Erythroid Leukemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These cytogenetic and molecular characteristics render current
      treatment approaches largely ineffective, and signal an urgent need for
      novel therapeutic modalities.
    explanation: A dedicated review corroborates that current treatment approaches are largely ineffective given the disease's cytogenetic/molecular characteristics.
  - reference: PMID:38892446
    reference_title: "Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The median OS of AlloBMT recipients was 89 months, compared to 5 months
      for those who did not undergo AlloBMT
    explanation: >-
      Shows that reaching allogeneic transplant, rather than any particular
      drug regimen, is associated with markedly longer survival in a larger,
      more heterogeneous cohort than the Mayo series.
notes: >-
  Classification of this entity has changed substantially and remains
  actively debated; see the `definitions` and `discussions` blocks. In brief:
  FAB/WHO 2001-2008 recognized two subtypes by erythroid/blast percentage
  alone (M6a erythroid/myeloid and M6b pure erythroid); WHO 2016 eliminated
  M6a as a distinct AML entity, reclassifying most such cases as MDS, AML-MR,
  or AML/MDS-NOS by blast percentage; WHO-HAEM5 (2022) retains and renames
  M6b as the current, TP53-centered AEL/pure erythroid leukemia entity used
  as the primary scope of this file; and the ICC (2022) instead folds pure
  erythroid leukemia into a broader "AML with mutated TP53" category rather
  than keeping a separately named erythroid entity. A comprehensive genomic
  study (Iacobucci et al., PMID:30926971) argues the WHO 2016 reclassification
  of the erythroid/myeloid category was not well supported by mutational
  data, so this boundary should be read as unsettled rather than as a fixed
  fact. Curators extending this entry should not assume any single historical
  source's "AEL" or "M6" definition is interchangeable with the current
  WHO-HAEM5 scope used here.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Acute Erythroid Leukemia: Disease Characteristics Research Report
Edison Scientific Literature 22 citations 2026-08-26T16:39:26.180666

Acute Erythroid Leukemia: Disease Characteristics Research Report

Evidence cutoff: literature prioritized through 2024. Because acute erythroid leukemia (AEL) is exceptionally rare and its definition has repeatedly changed, most clinical evidence consists of retrospective cohorts, registry studies, case series, and mechanistic models rather than prospective AEL-specific trials. Numerical comparisons across historical studies must therefore be interpreted cautiously.

Executive summary

AEL is a rare, rapidly progressive erythroid-lineage acute leukemia centered in bone marrow. The WHO 2022/WHO-HAEM5 morphologic entity requires ≥80% erythroid precursors and ≥30% proerythroblasts in marrow. By contrast, the 2022 International Consensus Classification (ICC) generally subsumes the corresponding TP53-mutated disease under AML with mutated TP53, requiring a somatic TP53 variant allele fraction (VAF) >10% and the applicable blast/PEL criterion. Thus, “AEL,” “pure erythroid leukemia,” and historical “AML-M6” are not perfectly interchangeable across datasets. A 2024 expert review summarizes the current biology directly: “This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions.” [Fernandes et al., published 6 June 2024, DOI: https://doi.org/10.3390/ijms25116256] (fernandes2024acuteerythroidleukemia pages 2-4, fernandes2024acuteerythroidleukemia pages 1-2)

The disease primarily affects older adults, produces severe marrow failure, and has a median survival commonly measured in months. Intensive AML chemotherapy or hypomethylating agents may induce remission, but allogeneic hematopoietic-cell transplantation (allo-HCT) is the only established potentially curative strategy. TP53 loss, complex/monosomal cytogenetics, and erythroid-state BCL-XL dependence help explain chemotherapy resistance and possible relative resistance to venetoclax. No AEL-specific approved molecular therapy or prevention program exists. (fernandes2024acuteerythroidleukemia pages 1-2, fernandes2024acuteerythroidleukemia pages 12-14, fernandes2024acuteerythroidleukemia pages 11-12)

1. Disease information

Definition and classification

  • Category: rare hematologic malignancy; acute myeloid/erythroid-lineage leukemia.
  • MONDO: MONDO:0017858 (acute erythroid leukemia). OpenTargets recognizes this disease entity but returned no curated disease-specific target associations, illustrating the limited structured evidence base. (OpenTargets Search: acute erythroid leukemia)
  • Current WHO definition: marrow with ≥80% immature erythroid cells/erythroid precursors, including ≥30% proerythroblasts. (fernandes2024acuteerythroidleukemia pages 2-4, fernandes2024acuteerythroidleukemia pages 1-2)
  • ICC 2022: corresponding cases are generally classified as AML with mutated TP53 when there are ≥20% blood or marrow blasts—or pure erythroid leukemia morphology—and a somatic TP53 mutation with VAF >10%. (fernandes2024acuteerythroidleukemia pages 2-4, ohan2024anunusualcase pages 3-4)
  • Historical terminology: Di Guglielmo disease/erythroleukemia; FAB AML-M6; M6a erythroid/myeloid leukemia; M6b or pure erythroid leukemia (PEL). “Acute erythroleukemia” is also used, but older M6 cohorts include cases that would now be MDS or another genetically defined AML. (fernandes2024acuteerythroidleukemia pages 1-2)

A rare TP53-wild-type exception illustrates why morphology and genetics must both be recorded: a 2024 PEL-like case had normal 46,XY cytogenetics with NPM1 and NRAS, but no TP53 mutation; under modern systems it may instead be an NPM1-mutated myeloid neoplasm with erythroid predominance. [Ohan et al., July 2024, DOI: https://doi.org/10.1007/s12308-024-00588-5] (ohan2024anunusualcase pages 3-4)

Other identifiers: a unique OMIM disease entry is not established because AEL is predominantly an acquired somatic cancer, not a Mendelian disorder. ICD-10-CM generally places it within AML codes rather than a robust AEL-specific code; ICD-11 and MeSH similarly require classification under acute myeloid/erythroid leukemia concepts. Local coding should retain both the edition and morphology/genotype.

Evidence provenance: the report uses aggregated disease-level literature, registries, cohorts, and experimental studies—not individual EHR records. Case reports are identified as such.

2. Etiology, risk, and protective factors

AEL is usually an acquired clonal disease. Its proximal cause is accumulation of somatic genomic lesions in hematopoietic stem/progenitor cells, most characteristically multi-hit TP53 disruption plus chromosomal instability and erythroid differentiation/signaling abnormalities. It may arise de novo, after MDS or an MPN, or following cytotoxic chemotherapy/radiotherapy. Therapy-related and antecedent-MDS disease have especially short reported median survivals—approximately 2.3 and 2.6 months versus 3.9 months for de novo disease in one synthesis. (fernandes2024acuteerythroidleukemia pages 2-4)

Risk factors

  • Age: median diagnosis age approximately 67 years; reported distribution is bimodal, around ages 20 and 70. Older age likely reflects clonal hematopoiesis, accumulated mutations, antecedent myeloid disease, and treatment exposure. (fernandes2024acuteerythroidleukemia pages 2-4)
  • Sex: reported male:female ratio approximately 2.4:1. (fernandes2024acuteerythroidleukemia pages 2-4)
  • Antecedent disease: MDS, MPN, and other myeloid neoplasms are important clinical contexts.
  • Iatrogenic/environmental: previous alkylating agents, topoisomerase-II inhibitors, radiation, and benzene are plausible AML/AEL risks; AEL-specific attributable fractions are unavailable. (fernandes2024acuteerythroidleukemia pages 1-2)
  • Genetic susceptibility: no recurrent germline variant is established as a specific inherited cause. Germline TP53 cancer predisposition and inherited marrow-failure/AML-predisposition genes should be considered when age, phenotype, or family history is suggestive, but most TP53 lesions in AEL are somatic.

No validated genetic or lifestyle protective factor is known. Avoiding benzene and unnecessary ionizing radiation reduces general AML risk, but no study demonstrates AEL-specific prevention. There is also no established AEL-specific gene–environment interaction; a plausible model is that genotoxic exposure selects or generates TP53-defective clones, after which cooperating signaling/chromatin lesions impose erythroid lineage bias.

3. Phenotypes

The onset is generally acute or subacute and severe. Marrow replacement and ineffective erythropoiesis cause progressive cytopenias and constitutional symptoms.

  • Anemia—usually severe and nearly universal clinically; fatigue, exertional intolerance, dyspnea, and pallor follow. One review reports a median hemoglobin of 7.5, although the stated unit “g/L” is almost certainly a source/unit error and should not be propagated without checking the underlying cohort. Suggested HPO: HP:0001903. (fernandes2024acuteerythroidleukemia pages 2-4)
  • Thrombocytopenia—bleeding, bruising, or petechiae; HPO HP:0001873.
  • Neutropenia/pancytopenia—infection risk and fever; pancytopenia HPO HP:0001876, fever HP:0001945.
  • Pallor—HPO HP:0000980; largely downstream of anemia.
  • Hepatomegaly/splenomegaly—variable extramedullary erythroid/leukemic involvement; use separate HPO hepatomegaly and splenomegaly terms after identifier validation.
  • Hemolysis laboratory evidence—variable; possible increased bilirubin/LDH and reduced haptoglobin, but AEL-specific frequencies are not well quantified.
  • Marrow abnormalities—marked hypercellularity, erythroid predominance, dyserythropoiesis, and numerous immature proerythroblasts. Higher proerythroblast proportion is associated with poorer outcome. (fernandes2024acuteerythroidleukemia pages 2-4)

Symptoms progress rather than fluctuate without effective treatment. Quantitative phenotype penetrance and AEL-specific EQ-5D/SF-36 data are unavailable. Quality of life is severely affected through transfusion dependence, fatigue, bleeding/infection risk, repeated hospitalization, chemotherapy toxicity, and limited survival.

4. Genetic and molecular information

Core lesions

TP53 is the defining molecular hallmark of modern AEL/PEL. Reported mutation frequency varies dramatically with historical definitions—43.5% in a 92-patient cohort and 36.3% in a 58-patient cohort, but 100% in recent Mayo (41 cases) and MD Anderson (21 cases) series applying modern 2016–2022 concepts. The common multi-hit configuration is one mutated allele plus deletion/loss of the other, producing biallelic loss of function. These are somatic SNVs/indels and/or 17p deletion/copy-neutral LOH; population allele frequency is therefore not meaningfully represented by germline gnomAD frequency. (fernandes2024acuteerythroidleukemia pages 7-8)

Complex karyotype—at least three abnormalities—is nearly uniform in modern PEL cohorts. Recurrent lesions include −5/del(5q), −7/del(7q), trisomy 8, and 17p13/TP53 abnormalities. Complex and monosomal genomes reflect p53-deficient tolerance of DNA damage and mitotic errors. (fernandes2024acuteerythroidleukemia pages 4-5, fernandes2024acuteerythroidleukemia pages 2-4)

Additional recurrent/cooperating genes and lesions include:

  • EPOR/JAK2/STAT signaling: EPOR overexpression or amplification, JAK2 gain/JAK2V617F, and occasional EPOR/JAK2/ERG copy gains; one synthesis reports JAK2 variants in 30%, although estimates are strongly cohort-dependent. (fernandes2024acuteerythroidleukemia pages 4-5)
  • RAS/MAPK: NRAS, KRAS, PTPN11, NF1; one older cohort found NRAS/KRAS/FLT3 lesions in only 3/92 cases, demonstrating heterogeneity. (fernandes2024acuteerythroidleukemia pages 4-5, fagnan2021molecularlandscapesand pages 1-2)
  • Erythroid/transcriptional regulation: GATA1-pathway abnormalities in >25% in one analysis; GATA2, CEBPA, ERG, FLI1, CDX4, and rare NFIA::ETO2. (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 4-5)
  • Epigenetic/chromatin: TET2, DNMT3A, ASXL1, IDH2, BCOR/BCORL1. One cohort found epigenetic-regulator lesions in 33.3%, including eight TET2 nonsense and five DNMT3A mutations. (fernandes2024acuteerythroidleukemia pages 7-8)
  • Pediatric disease: NUP98 fusions appear enriched; one analysis reported 31.8% in the AEL category versus 6.7% in other pediatric AML, although the AEL denominator was very small. (fernandes2024acuteerythroidleukemia pages 8-10)
  • Rare actionable exceptions: NTRK1 alterations and NPM1/NRAS-mutated TP53-wild-type disease are reported, but these are not typical. (ohan2024anunusualcase pages 3-4, fagnan2021molecularlandscapesand pages 7-8)

ACMG germline labels should not be automatically applied to these tumor variants. Somatic clinical interpretation should use AMP/ASCO/CAP, ClinGen Somatic, OncoKB, or equivalent cancer frameworks. Paired normal testing is indicated when germline predisposition is suspected.

Epigenetics and modifiers

BCOR/BCORL1 loss disrupts noncanonical PRC1.1: the chromatin-targeting component remains localized but becomes uncoupled from the RING–PCGF repressive core, causing loss of repression, transcriptional activation of oncogenic targets, and treatment resistance. This is mechanistically supported in leukemia systems, although it is not unique to AEL. [Schaefer et al., published March 2022, DOI: https://doi.org/10.1158/2643-3230.BCD-21-0115] (fernandes2024acuteerythroidleukemia pages 7-8)

No validated modifier allele reliably predicts severity specifically within AEL. TP53 allelic state, complex karyotype, antecedent disease, age, and transplant eligibility currently carry more clinical value than individual secondary variants.

5. Environmental information

There is no infectious cause and no zoonotic or transmissible component. General myeloid-neoplasm exposures—benzene, ionizing radiation, tobacco-associated benzene, and previous leukemogenic chemotherapy—are relevant, but AEL-specific dose–response statistics are unavailable. Smoking cessation, occupational exposure controls, and radiation minimization are prudent general AML prevention measures, not proven AEL-specific interventions. (fernandes2024acuteerythroidleukemia pages 1-2)

6. Mechanism and pathophysiology

Causal chain

  1. Upstream clonal initiation: an HSPC acquires TP53 dysfunction, frequently followed by loss of the second allele. This permits survival after genotoxic stress, defective apoptosis/checkpoint control, and chromosomal instability.
  2. Cooperating lineage/signaling lesions: gains or mutations involving EPOR/JAK2/STAT, RAS/MAPK, ERG, GATA1/GATA2/CEBPA, or BCOR/DNMT3A remodel growth signaling and lineage programs.
  3. Erythroid commitment with maturation arrest: GATA1/KLF1/ZFPM1-centered chromatin and transcription programs become distorted; immature erythroid progenitors proliferate but fail terminal differentiation.
  4. Leukemic expansion: EPOR activates JAK2–STAT, PI3K–AKT, and ERK pathways, promoting survival and proliferation. RAS12V can block EPO-induced differentiation in murine erythroleukemia cells. (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 4-5)
  5. Clinical injury: marrow replacement and ineffective hematopoiesis cause anemia, thrombocytopenia, neutropenia, infection, bleeding, hypoxia/fatigue, and occasionally hepatic/splenic infiltration.
  6. Resistance/relapse: multi-hit TP53, complex cytogenetics, chromatin dysregulation, and an erythroid BCL-XL survival state reduce chemotherapy durability and may blunt BCL2-selective venetoclax activity. (fernandes2024acuteerythroidleukemia pages 12-14, fernandes2024acuteerythroidleukemia pages 16-18)

Functional and multi-omics findings

Transcriptomic studies separate signaling/TP53/chromatin-associated groups, but no single-cell or spatial atlas is sufficiently validated for routine AEL classification. GATA2 plus biallelic CEBPA lesions increase accessibility at erythroid GATA1/ZFPM1/KLF1 motifs and decrease myeloid-motif accessibility in models. EPOR/JAK2/ERG amplification and high BCL-XL expression identify potential dependencies. AEL-specific proteomics, metabolomics, and lipidomics remain major evidence gaps. (fernandes2024acuteerythroidleukemia pages 4-5, fagnan2021molecularlandscapesand pages 6-7, fernandes2024acuteerythroidleukemia pages 12-14)

Suggested annotations include GO:0030218 erythrocyte differentiation, GO:0008283 cell proliferation, GO:0097190 apoptotic signaling, GO:0007259 JAK–STAT cascade, GO:0006325 chromatin organization; CL proerythroblast/erythroid progenitor and hematopoietic stem/progenitor cell terms.

7. Anatomical structures affected

The bone marrow (UBERON:0002371) is primary; blood (UBERON:0000178) reflects cytopenias and circulating blasts. Secondary involvement may include spleen (UBERON:0002106) and liver (UBERON:0002107), producing hepatosplenomegaly. There is no lateralization. At tissue/cell level, malignant proerythroblasts and erythroid progenitors displace normal erythroid, myeloid, and megakaryocytic hematopoiesis. At subcellular level, the nucleus/chromatin, transcriptional machinery, cytokine receptors/plasma membrane, and downstream cytoplasmic kinase cascades are central.

8. Temporal development

Typical onset is acute/subacute in late adulthood, although pediatric and young-adult peaks occur. Untreated disease progresses rapidly to profound marrow failure. There is no AJCC solid-tumor staging system; clinically relevant states are newly diagnosed, refractory, remission/MRD-positive or negative, relapsed, and post-transplant. Spontaneous durable remission is not expected. The principal intervention window is rapid diagnostic work-up followed by remission induction and, in eligible responders, prompt allo-HCT.

9. Inheritance and population

AEL represents approximately 2% of AML in historical estimates, but its true incidence cannot be reliably inferred because modern WHO/ICC reclassify many old M6 cases. Median age is about 67 years and males predominate approximately 2.4:1. No robust ethnic, founder, consanguinity, carrier-frequency, or geographic effect has been established. (fernandes2024acuteerythroidleukemia pages 1-2, fernandes2024acuteerythroidleukemia pages 2-4)

AEL is not ordinarily inherited; therefore penetrance, anticipation, carrier state, and germline mosaicism are not generally applicable. If constitutional TP53 or another predisposition syndrome is demonstrated, inheritance and counseling follow that syndrome rather than AEL itself.

10. Diagnostics

Recommended workflow

  1. CBC, differential, reticulocytes, blood smear: define anemia, thrombocytopenia, neutropenia, and circulating abnormal erythroblasts; add coagulation, CMP, LDH, uric acid, bilirubin, haptoglobin, type-and-screen, viral serologies, and infection cultures as clinically indicated.
  2. Bone-marrow aspirate and core biopsy: quantify total erythroid precursors and proerythroblasts; assess dyserythropoiesis, fibrosis, and nonerythroid blasts. A dry or hemodilute aspirate makes the core and immunohistochemistry especially important.
  3. Flow cytometry/IHC: immature erythroid cells are typically strongly CD71 positive and may express E-cadherin, CD36, CD68, Gerbich antigen, dim glycophorin A/hemoglobin, and spectrin. They are generally MPO-, HLA-DR-, and CD33-negative. Early proerythroblasts can lack mature glycophorin A, so a negative single erythroid marker does not exclude AEL. (fernandes2024acuteerythroidleukemia pages 2-4)
  4. Cytogenetics: conventional karyotype plus targeted FISH/CNV testing for chromosomes 5, 7, 8, 17p/TP53 and other suspected rearrangements.
  5. Molecular testing: rapid myeloid NGS including TP53 with VAF and copy-number/LOH assessment; NPM1, FLT3, CEBPA, RUNX1, ASXL1, BCOR/BCORL1, DNMT3A, TET2, IDH1/2, NRAS/KRAS, JAK2, GATA2, and fusion-capable RNA sequencing. Determining TP53 allelic state is more informative than reporting mutation presence alone. (fernandes2024acuteerythroidleukemia pages 12-14, fernandes2024acuteerythroidleukemia pages 7-8)
  6. Germline assessment: cultured skin fibroblast or another nonhematopoietic source when age/family history, variant pattern, or transplant planning raises hereditary-predisposition concern.

WES/WGS can identify unusual structural or noncoding lesions but does not replace rapid karyotype, FISH, RNA fusion testing, and clinically validated myeloid panels. Chromosomal microarray can refine copy-number/LOH, while mitochondrial and repeat-expansion testing have no routine role. Imaging is used for symptoms, infection, or organ involvement—not primary diagnosis. No population screening test exists.

Differential diagnosis

Important alternatives are MDS with erythroid predominance, AML with myelodysplasia-related genetics, TP53-mutated AML without AEL morphology, NPM1-mutated AML with erythroid predominance, acute megakaryoblastic leukemia, acute undifferentiated leukemia, B-ALL, reactive erythroid hyperplasia after hemolysis/EPO therapy, megaloblastic anemia, parvovirus-related giant pronormoblasts, and metastatic nonhematopoietic malignancy. Integrated morphology, broad IHC/flow, cytogenetics, and sequencing are required because proerythroblasts may mimic lymphoblasts or megakaryoblasts. (fernandes2024acuteerythroidleukemia pages 12-14, ohan2024anunusualcase pages 3-4)

11. Outcome and prognosis

Recent-definition AEL has a typical median survival of 3–9 months. A 41-patient TP53-mutated cohort had mean OS of approximately 3.3 months. In an international pooled historical cohort of 217 patients, median OS was 11.1 months, PFS 7.1 months, and one-year survival 49%; this more favorable estimate likely reflects older definitions and selection. (fernandes2024acuteerythroidleukemia pages 1-2, fernandes2024acuteerythroidleukemia pages 10-11, fernandes2024acuteerythroidleukemia pages 8-10)

Age strongly modifies outcome. Historical registry data found median OS of 69 months and five-year survival of 55.01% among 50 treated children, versus median OS around five months among 918 adults. These pediatric figures should not be generalized to WHO-2022 TP53-driven adult AEL. (fernandes2024acuteerythroidleukemia pages 10-11)

Adverse factors include older age, multi-hit TP53, complex/monosomal karyotype, greater proerythroblast burden, therapy-related or antecedent-MDS disease, refractory disease, poor performance status, and inability to undergo allo-HCT. Transplant data are strongly selected but clinically important: one cohort reported median OS 89 months with HCT versus five months without HCT (p=0.003). (fernandes2024acuteerythroidleukemia pages 11-12, fernandes2024acuteerythroidleukemia pages 10-11)

Major morbidity and mortality arise from progressive leukemia, infection/sepsis, bleeding, severe anemia, organ infiltration, treatment toxicity, relapse, and transplant complications. Validated AEL-specific patient-reported outcome or long-term disability datasets are lacking.

12. Treatment and current implementation

Treatment should occur at an AML/transplant center with pathology review because classification determines both risk and trial eligibility.

Established approaches

  • Fit patient: AML-style intensive induction, commonly cytarabine plus an anthracycline, followed by consolidation and rapid evaluation for allo-HCT. In a historical 122-patient analysis, intensive chemotherapy produced 72% overall response and 66% complete remission; median OS was 10.5 months and one-year survival 46.7%. These results predate current definitions. (fernandes2024acuteerythroidleukemia pages 11-12, fernandes2024acuteerythroidleukemia pages 10-11)
  • Older/unfit patient: azacitidine or decitabine, often following contemporary AML practice with venetoclax. In historical AEL cohorts, HMA therapy showed median OS around 13.7 months and first-line PFS 9.4 months versus 3.4 months when used later. However, erythroid/megakaryocytic differentiation can create BCL-XL rather than BCL2 dependence, potentially limiting venetoclax benefit. (fernandes2024acuteerythroidleukemia pages 11-12, fernandes2024acuteerythroidleukemia pages 10-11)
  • Allo-HCT: only established potentially curative modality; pursue in remission when feasible, acknowledging high relapse and nonrelapse mortality. (fernandes2024acuteerythroidleukemia pages 1-2, fernandes2024acuteerythroidleukemia pages 11-12)
  • Genotype-directed AML drugs: FLT3, IDH1, or IDH2 inhibitors are reasonable only when the corresponding actionable lesion is present; such variants are uncommon in prototypic AEL.
  • Supportive care: irradiated/leukoreduced red-cell and platelet transfusions, antimicrobial treatment/prophylaxis according to neutropenia and regimen, tumor-lysis prevention, bleeding management, growth-factor use when appropriate, nutrition, palliative care, and transplant support.

Suggested NCIT concepts: Acute Myeloid Leukemia Chemotherapy, Cytarabine, Daunorubicin/Idarubicin, Azacitidine, Decitabine, Venetoclax, Allogeneic Hematopoietic Stem Cell Transplantation, Blood Product Transfusion, and Best Supportive Care; exact NCIT identifiers should be validated during curation.

Experimental approaches

Preclinical vulnerabilities include EPOR/JAK2 inhibition with ruxolitinib, PARP inhibition with talazoparib, combined BCL-XL/JAK2 blockade, and CDK7/CDK9 inhibition. Larotrectinib prevented disease beyond 100 days in an NTRK1/TP53-comutant mouse transplant model, but this applies only to rare NTRK-driven disease. (fernandes2024acuteerythroidleukemia pages 4-5, fagnan2021molecularlandscapesand pages 7-8, fernandes2024acuteerythroidleukemia pages 12-14)

A phase-I decitabine–talazoparib study in 25 relapsed/refractory AML patients—not an AEL-specific cohort—reported 8% CR/CRi and 12% hematologic improvement. This is hypothesis-generating, not evidence of AEL efficacy. CAR-T, gene therapy, RNA therapy, and checkpoint blockade remain investigational without established AEL-specific benefit. (fernandes2024acuteerythroidleukemia pages 12-14)

ClinicalTrials.gov: NCT02861651, “Molecular Characterization of Acute Erythroid Leukemia (M6-AML) Using Targeted Next-generation Sequencing,” was a completed observational study with planned enrollment of 40. No contemporary randomized interventional trial dedicated specifically to WHO-2022 AEL was identified.

Surgery and radiotherapy have no routine leukemia-directed role. Pharmacogenomic dosing follows the drugs used rather than an AEL-specific rule.

13. Prevention

There is no vaccine, chemoprevention, newborn screen, carrier screen, or population-based AEL screening program. Primary prevention is limited to general reduction of benzene, tobacco smoke, unnecessary radiation, and avoidable leukemogenic exposure. Secondary prevention consists of monitoring individuals with MDS/MPN, therapy-related risk, unexplained cytopenias, or recognized germline predisposition; routine screening of asymptomatic average-risk people is unsupported. Tertiary prevention includes infection and bleeding prophylaxis, transfusion support, relapse/MRD surveillance where a trackable molecular marker exists, and transplant-related prophylaxis. Genetic counseling is appropriate only when constitutional predisposition is suspected or confirmed.

14. Other species and natural disease

No well-established, naturally occurring veterinary disease is recognized as a standardized homolog of human WHO-defined AEL. Sporadic erythroid leukemias can occur in animals, but breed-specific incidence, VBO mappings, and conserved initiating variants are not adequately established. There is no zoonotic potential or cross-species transmission. Comparative relevance derives mainly from induced Mus musculus models (NCBI Taxonomy 10090), not natural disease.

15. Model organisms and experimental systems

Genetically engineered or transplant mouse models reproduce major features:

  • JAK2V617F + TP53 loss: serially transplantable CD71+/Ter119− erythroid leukemia with anemia and hepatosplenomegaly.
  • ERG overexpression + mutant TP53: fatal erythroleukemia within approximately 60 days after transplantation.
  • NFIA::ETO2 + TP53R248Q: fully penetrant, transplantable disease with anemia, thrombocytopenia, hepatosplenomegaly, and circulating erythroid progenitors.
  • Biallelic CEBPA + GATA2 mutation: erythroleukemia in about 40% of triple-transgenic mice, with erythroid-biased chromatin accessibility.
  • BCOR/DNMT3A or multiplex TP53/BCOR/DNMT3A lesions: models epigenetic cooperation and provides platforms for PARP, CDK, and signaling-inhibitor testing. (fernandes2024acuteerythroidleukemia pages 7-8, fagnan2021molecularlandscapesand pages 7-8, fagnan2021molecularlandscapesand pages 6-7)

Cellular systems include murine SKT6 erythroleukemia cells, human AML/erythroid leukemia cell lines, primary patient cells, and xenografts. Their strengths are controlled causal testing and rapid drug evaluation. Limitations include engineered lesion combinations, murine erythroid markers and cytokine biology, incomplete human marrow/immune microenvironments, and failure to reproduce the full genomic complexity and age-related clonal evolution of human AEL.

Curated ontology and knowledge-base mapping

The following compact table consolidates recommended disease, phenotype, anatomy, cell, pathway, gene, and intervention annotations. Entries marked for verification should be checked against the current ontology release before database ingestion.

Domain Recommended term/identifier AEL evidence/meaning Confidence or caveat
Disease ontology Acute erythroid leukemia — MONDO:00017858 / MONDO_0017858 Current disease-level identifier for AEL; useful anchor because classification has shifted between WHO and ICC systems (fernandes2024acuteerythroidleukemia pages 1-2, OpenTargets Search: acute erythroid leukemia) High confidence for MONDO mapping; formatting may vary by source
Disease terminology Acute erythroid leukemia (AEL) Rare, aggressive AML subtype centered on marrow erythroid precursor predominance (fernandes2024acuteerythroidleukemia pages 1-2) High confidence
Historical synonym AML-M6 Historical FAB terminology for acute erythroleukemia/erythroid leukemia (fernandes2024acuteerythroidleukemia pages 1-2) High confidence; historical, not preferred current label
Historical synonym Pure erythroid leukemia (PEL) Historic subtype term; in current frameworks often absorbed differently, especially under TP53-mutated AML concepts in ICC (fernandes2024acuteerythroidleukemia pages 1-2, ohan2024anunusualcase pages 3-4) High confidence; classification caveat important
Classification note WHO 2022 AEL definition WHO 2022 uses marrow morphology with ≥30% proerythroblasts and ≥80% erythroid precursors/cellularity (fernandes2024acuteerythroidleukemia pages 2-4, fernandes2024acuteerythroidleukemia pages 1-2) High confidence
Classification note ICC 2022: AML with mutated TP53 ICC framework places many former PEL/AEL cases under AML with mutated TP53 when criteria are met (fernandes2024acuteerythroidleukemia pages 2-4, ohan2024anunusualcase pages 3-4) High confidence; not identical to WHO morphology-based entity
HPO phenotype Anemia — HP:0001903 Common presentation; severe anemia is a hallmark laboratory/clinical abnormality in AEL (fernandes2024acuteerythroidleukemia pages 2-4) High confidence
HPO phenotype Thrombocytopenia — HP:0001873 Common cytopenia in AEL and in experimental models recapitulating disease (fagnan2021molecularlandscapesand pages 7-8) High confidence
HPO phenotype Fever — HP:0001945 Reported presenting symptom in clinical cohorts (fernandes2024acuteerythroidleukemia pages 2-4) High confidence
HPO phenotype Pallor — HP:0000980 Reported clinical sign, usually secondary to profound anemia (fernandes2024acuteerythroidleukemia pages 2-4) Moderate confidence; ID should be verified in implementation
HPO phenotype Hepatosplenomegaly — term only, ID verification required Reported in clinical cohorts and several mouse/transplant models (fernandes2024acuteerythroidleukemia pages 2-4, fagnan2021molecularlandscapesand pages 7-8, fagnan2021molecularlandscapesand pages 6-7) Concept confident; exact HPO ID not asserted here
HPO phenotype Pancytopenia — HP:0001876 Can be present at diagnosis; reflects marrow failure from leukemic erythroid replacement Moderate confidence; exact AEL citation indirect, ID should be verified locally
HPO phenotype Hemolysis — term only, ID verification required Evidence of hemolysis described in clinical presentation summaries (fernandes2024acuteerythroidleukemia pages 2-4) Concept confident; exact HPO ID not asserted here
Cell ontology Proerythroblast / erythroid progenitor — CL term, ID verification required Central malignant population in WHO-defined AEL; CD71-high immature erythroid precursors dominate marrow (fernandes2024acuteerythroidleukemia pages 2-4) Cell concept high confidence; precise CL mapping requires verification
Cell ontology Hematopoietic stem/progenitor cell — CL term, ID verification required Likely disease-propagating compartment in experimental systems; TP53-mutant HSPCs plus cooperating lesions can generate erythroleukemia (fernandes2024acuteerythroidleukemia pages 7-8, fagnan2021molecularlandscapesand pages 6-7) Concept high confidence; exact CL ID verify
Anatomy Bone marrow — UBERON:0002371 Primary disease site; biopsy-based diagnosis and dominant erythroid hypercellularity (fernandes2024acuteerythroidleukemia pages 2-4, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
Anatomy Blood — UBERON:0000178 Peripheral blasts/cytopenias can support diagnosis and monitoring (fernandes2024acuteerythroidleukemia pages 2-4) High confidence
Anatomy Spleen — UBERON:0002106 Splenomegaly/erythroid infiltration reported in patients and mouse models (fernandes2024acuteerythroidleukemia pages 2-4, fagnan2021molecularlandscapesand pages 6-7) High confidence
Anatomy Liver — UBERON:0002107 Hepatomegaly or liver involvement may occur in aggressive erythroid disease/model systems (fernandes2024acuteerythroidleukemia pages 2-4, fagnan2021molecularlandscapesand pages 7-8) High confidence
GO biological process Erythrocyte differentiation — GO:0030218 Core disrupted process; leukemic cells show erythroid lineage commitment with terminal maturation block (fernandes2024acuteerythroidleukemia pages 4-5, fagnan2021molecularlandscapesand pages 1-2) High confidence
GO biological process Cell proliferation — GO:0008283 Unchecked expansion of immature erythroid progenitors is central to pathogenesis (fernandes2024acuteerythroidleukemia pages 1-2, fagnan2021molecularlandscapesand pages 1-2) High confidence
GO biological process Apoptotic signaling pathway — GO:0097190 TP53 dysfunction alters apoptosis control and contributes to treatment resistance (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 1-2) Moderate confidence; broad process mapping
GO biological process JAK-STAT cascade / signaling — GO:0007259 EPOR/JAK2/STAT signaling is recurrently implicated, especially in EPOR/JAK2-gain cases (fernandes2024acuteerythroidleukemia pages 4-5, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
GO biological process Chromatin organization — GO:0006325 BCOR/PRC1.1 and epigenetic regulator mutations support chromatin dysregulation in AEL biology (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
GO cellular component Nucleus — GO:0005634 Many driver lesions affect nuclear transcription/chromatin regulators (TP53, GATA factors, BCOR, DNMT3A, TET2) (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
GO cellular component Chromatin — GO:0000785 Relevant compartment for PRC1.1/BCOR and transcription factor dysregulation (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
Gene TP53 Dominant molecular hallmark; often biallelically inactivated and linked to complex karyotype, poor prognosis (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 1-2) High confidence
Gene EPOR Upregulated/amplified in subset; supports erythroid growth signaling (fernandes2024acuteerythroidleukemia pages 4-5, fernandes2024acuteerythroidleukemia pages 12-14) Moderate-high confidence
Gene JAK2 Recurrent signaling lesion; JAK2V617F and EPOR/JAK2 pathway activation implicated; preclinical ruxolitinib sensitivity reported (fernandes2024acuteerythroidleukemia pages 4-5, fagnan2021molecularlandscapesand pages 6-7, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
Gene GATA1 Master erythroid regulator; dysregulation contributes to failed maturation (fernandes2024acuteerythroidleukemia pages 4-5, fernandes2024acuteerythroidleukemia pages 1-2) High confidence
Gene CEBPA Recurrent/cooperating transcription-factor alteration; with GATA2 can drive erythroid leukemia phenotypes in models (fernandes2024acuteerythroidleukemia pages 7-8, fagnan2021molecularlandscapesand pages 6-7) Moderate-high confidence
Gene GATA2 Recurrent in exome studies and cooperating lesion in erythroid leukemogenesis (fernandes2024acuteerythroidleukemia pages 7-8, fagnan2021molecularlandscapesand pages 6-7) Moderate-high confidence
Gene BCOR Epigenetic/chromatin regulator; cooperating driver in models and part of PRC1.1 dysfunction axis (fernandes2024acuteerythroidleukemia pages 12-14) High confidence
Gene DNMT3A Recurrent epigenetic regulator mutation; cooperates with BCOR in mouse AEL models (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 12-14) High confidence
Gene TET2 Recurrent epigenetic regulator mutation in clinical cohorts (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 8-10) High confidence
Gene ERG Gain/upregulation cooperates with TP53-mutant HSPCs to induce erythroleukemia in mice (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 4-5) Moderate-high confidence
Gene family RAS pathway (KRAS, NRAS) Recurrent cooperating signaling lesions; can combine with TP53 loss and impair erythroid differentiation (fernandes2024acuteerythroidleukemia pages 7-8, fernandes2024acuteerythroidleukemia pages 4-5) High confidence for pathway-level mapping
NCIT intervention Intensive AML chemotherapy — NCIT concept, ID verification required Real-world AEL treatment backbone; retrospective cohorts show ORR/CR but short median OS (fernandes2024acuteerythroidleukemia pages 11-12, fernandes2024acuteerythroidleukemia pages 10-11) Concept confident; exact NCIT code verify
NCIT intervention Azacitidine — NCIT concept, ID verification required Used as HMA frontline/low-intensity therapy; some cohorts suggest longer OS/PFS than expected historical controls (fernandes2024acuteerythroidleukemia pages 10-11, fernandes2024acuteerythroidleukemia pages 8-10) Concept confident; AEL-specific evidence retrospective
NCIT intervention Decitabine — NCIT concept, ID verification required Used in AML/MDS-style therapy and in experimental combinations such as with talazoparib (fernandes2024acuteerythroidleukemia pages 12-14) Concept confident; direct AEL-specific efficacy limited
NCIT intervention Venetoclax — NCIT concept, ID verification required Used by AML extrapolation; efficacy may be limited in erythroid/megakaryocytic states with BCL-XL dependence (fernandes2024acuteerythroidleukemia pages 11-12, fernandes2024acuteerythroidleukemia pages 16-18) Moderate confidence; disease-specific resistance caveat important
NCIT intervention Allogeneic hematopoietic stem cell transplantation — NCIT concept, ID verification required Only potentially curative modality; major survival advantage in retrospective AEL cohorts (fernandes2024acuteerythroidleukemia pages 11-12, fernandes2024acuteerythroidleukemia pages 10-11) High confidence for concept; selection bias caveat
NCIT intervention Ruxolitinib — NCIT concept, ID verification required Preclinical sensitivity in EPOR/JAK2-driven AEL models/xenografts (fernandes2024acuteerythroidleukemia pages 4-5, fernandes2024acuteerythroidleukemia pages 12-14) Moderate confidence; investigational for AEL
NCIT intervention Talazoparib — NCIT concept, ID verification required PARP inhibitor with preclinical rationale in TP53-mutant AEL; early AML trial data not AEL-specific (fagnan2021molecularlandscapesand pages 7-8, fernandes2024acuteerythroidleukemia pages 12-14) Moderate confidence; not established standard
NCIT intervention Transfusion/supportive care — NCIT concept, ID verification required Important because severe cytopenias, infection risk, and frailty are common; usually implemented as AML supportive management High confidence for standard supportive role; direct AEL-specific trial data sparse

Table: This table maps acute erythroid leukemia to practical ontology, anatomy, cell-type, pathway, gene, phenotype, and intervention concepts for knowledge-base use. It highlights where current evidence is strong and where identifier verification is still needed because AEL classification and reporting remain heterogeneous.

Evidence appraisal and major gaps

The strongest conclusions are the current WHO morphologic definition, ICC TP53 framework, association with multi-hit TP53 and complex 5/7/17p cytogenetics, marrow-failure phenotype, extremely poor adult prognosis, and the potential curative role of allo-HCT. Less certain are exact incidence, mutation frequencies outside TP53, comparative efficacy of intensive chemotherapy versus HMA–venetoclax, and purported targeted dependencies. Most treatment statistics derive from historical “AML-M6/AEL” populations that do not map cleanly onto WHO-2022 disease. Priority research needs are prospective WHO/ICC-annotated registries, AEL-specific single-cell/multi-omic profiling, functional studies using primary human cells, and molecularly stratified trials addressing TP53, EPOR/JAK2, BCL-XL, chromatin, and DNA-repair vulnerabilities. (fernandes2024acuteerythroidleukemia pages 12-14, fernandes2024acuteerythroidleukemia pages 4-5)

References

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  3. (fernandes2024acuteerythroidleukemia pages 12-14): Priyanka Fernandes, Natalie Waldron, Theodora Chatzilygeroudi, Nour Sabiha Naji, and Theodoros Karantanos. Acute erythroid leukemia: from molecular biology to clinical outcomes. International Journal of Molecular Sciences, 25:6256, Jun 2024. URL: https://doi.org/10.3390/ijms25116256, doi:10.3390/ijms25116256. This article has 18 citations.

  4. (fernandes2024acuteerythroidleukemia pages 11-12): Priyanka Fernandes, Natalie Waldron, Theodora Chatzilygeroudi, Nour Sabiha Naji, and Theodoros Karantanos. Acute erythroid leukemia: from molecular biology to clinical outcomes. International Journal of Molecular Sciences, 25:6256, Jun 2024. URL: https://doi.org/10.3390/ijms25116256, doi:10.3390/ijms25116256. This article has 18 citations.

  5. (OpenTargets Search: acute erythroid leukemia): Open Targets Query (acute erythroid leukemia, 40 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

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  8. (fernandes2024acuteerythroidleukemia pages 4-5): Priyanka Fernandes, Natalie Waldron, Theodora Chatzilygeroudi, Nour Sabiha Naji, and Theodoros Karantanos. Acute erythroid leukemia: from molecular biology to clinical outcomes. International Journal of Molecular Sciences, 25:6256, Jun 2024. URL: https://doi.org/10.3390/ijms25116256, doi:10.3390/ijms25116256. This article has 18 citations.

  9. (fagnan2021molecularlandscapesand pages 1-2): Alexandre Fagnan, Maria-Riera Piqué-Borràs, Samantha Tauchmann, Thomas Mercher, and Juerg Schwaller. Molecular landscapes and models of acute erythroleukemia. HemaSphere, 5:e558, Apr 2021. URL: https://doi.org/10.1097/hs9.0000000000000558, doi:10.1097/hs9.0000000000000558. This article has 14 citations and is from a peer-reviewed journal.

  10. (fernandes2024acuteerythroidleukemia pages 8-10): Priyanka Fernandes, Natalie Waldron, Theodora Chatzilygeroudi, Nour Sabiha Naji, and Theodoros Karantanos. Acute erythroid leukemia: from molecular biology to clinical outcomes. International Journal of Molecular Sciences, 25:6256, Jun 2024. URL: https://doi.org/10.3390/ijms25116256, doi:10.3390/ijms25116256. This article has 18 citations.

  11. (fagnan2021molecularlandscapesand pages 7-8): Alexandre Fagnan, Maria-Riera Piqué-Borràs, Samantha Tauchmann, Thomas Mercher, and Juerg Schwaller. Molecular landscapes and models of acute erythroleukemia. HemaSphere, 5:e558, Apr 2021. URL: https://doi.org/10.1097/hs9.0000000000000558, doi:10.1097/hs9.0000000000000558. This article has 14 citations and is from a peer-reviewed journal.

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  13. (fagnan2021molecularlandscapesand pages 6-7): Alexandre Fagnan, Maria-Riera Piqué-Borràs, Samantha Tauchmann, Thomas Mercher, and Juerg Schwaller. Molecular landscapes and models of acute erythroleukemia. HemaSphere, 5:e558, Apr 2021. URL: https://doi.org/10.1097/hs9.0000000000000558, doi:10.1097/hs9.0000000000000558. This article has 14 citations and is from a peer-reviewed journal.

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