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.

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

1. (fernandes2024acuteerythroidleukemia pages 2-4): 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.

2. (fernandes2024acuteerythroidleukemia pages 1-2): 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.

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.

6. (ohan2024anunusualcase pages 3-4): Hovsep Ohan, Juan Gomez-Gelvez, Yulei Shen, Sharmila Ghosh, John Carey, Kedar Inamdar, and Wei Liu. An unusual case of pure erythroid leukemia with normal karyotype and npm1 mutation. Journal of hematopathology, 17:163-166, Jul 2024. URL: https://doi.org/10.1007/s12308-024-00588-5, doi:10.1007/s12308-024-00588-5. This article has 0 citations.

7. (fernandes2024acuteerythroidleukemia pages 7-8): 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.

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.

12. (fernandes2024acuteerythroidleukemia pages 16-18): 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.

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.

14. (fernandes2024acuteerythroidleukemia pages 10-11): 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.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.