Chronic Myeloid Leukemia, BCR-ABL1 Positive

MONDO:0011996 Pathograph 13 Show in embeddings browser myeloid leukemia

Chronic myeloid leukemia (CML), BCR-ABL1 positive, is a myeloproliferative neoplasm characterized by the Philadelphia chromosome, resulting from a reciprocal translocation t(9;22)(q34;q11) that creates the BCR-ABL1 fusion gene. The constitutively active BCR-ABL1 tyrosine kinase drives uncontrolled myeloid cell proliferation. CML is the paradigmatic example of oncogene addiction and targeted therapy success, with tyrosine kinase inhibitors transforming it from a fatal disease to a manageable chronic condition. This entry covers BCR-ABL1 positive CML, which represents approximately 95% of all CML cases.

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9
Pathophys.
1
Histopath.
7
Phenotypes
1
Gaps
13
Pathograph
1
Genes
5
Medical Actions
2
Deep Research
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Classifications

ICD-O Morphology
Leukemia
Harrison's Part
ONCOLOGY HEMATOLOGY
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Discussions and Knowledge Gaps

1
Does CDH2 (N-cadherin) mediated GSK3β-sensitive suppression of proliferation observed in K562 leukemia cells represent a tractable therapeutic vulnerability in human CML, or is it a cell-line artifact without relevance to BCR-ABL1 driven pathophysiology?
HUMAN MODEL MISMATCH OPEN cml_cdh2_gsk3beta_translational_mismatch
Attached to
pathophysiology#Uncontrolled Myeloid Proliferation pathophysiology#Constitutive Tyrosine Kinase Activation pathophysiology#PI3K-AKT Pathway Activation pathophysiology#JAK-STAT Pathway Activation
K562 CML cells represent a well-established model but may diverge from primary CML stem cells and patient-derived xenografts in GSK3β signaling and CDH2 expression context. CDH2 exhibits pan-cancer context-dependent effects, suggesting that anti-proliferative phenotype in K562 cells may not generalize to human CML. The paper's own conclusion notes "the precise molecular mechanism remains unresolved" and identifies this as a "therapeutic vulnerability in this model" — language that appropriately caveat-gates claims to the K562 cell line. Clarifying whether the CDH2-GSK3β axis operates as a disease mechanism (not just in vitro drug target) is mechanistically meaningful for CML's relationship to Wnt/β-catenin and MAPK checkpoint signaling.
Proposed experiments
CDH2-GSK3β axis validation in primary CML progenitors and patient-derived xenografts
gene-perturbation proliferation assay in primary progenitors and xenografts Relation: this experiment is of type this experiment type This experiment is of type gene-perturbation proliferation assay in primary progenitors and xenografts.
exp_cml_cdh2_gsk3beta_primary_cells
Quantify CDH2 and GSK3β expression levels in primary CML stem cells (CD34+), patient-derived xenografts (PDX), and K562 cells to determine whether K562 model recapitulates the expression and signaling context of human disease. Test whether CDH2 overexpression or GSK3β inhibition (CHIR-99,021) suppresses proliferation in primary human CML progenitors or PDX models matching K562 phenotype. If the effect does not replicate, the mechanism is K562-specific.
Model systems
Primary CML CD34+ progenitor culture
Patient-derived CD34+ chronic myeloid leukemia stem/progenitor cells, the primary-cell context against which the K562 CDH2-GSK3β phenotype is tested for translational validity.
PRIMARY CELL CULTURE
CML patient-derived xenograft (PDX)
In vivo engraftment of primary CML cells used to assess whether CDH2 overexpression or GSK3β inhibition reproduces the K562 anti-proliferative effect in a disease-faithful microenvironment.
OTHER
K562 CML cell line
The immortalized BCR-ABL1-positive cell line in which the original CDH2-GSK3β-sensitive anti-proliferative effect was observed.
CELL LINE
Mechanistic intersection of CDH2-GSK3β axis with BCR-ABL1 signaling
signaling-pathway epistasis mapping assay Relation: this experiment is of type this experiment type This experiment is of type signaling-pathway epistasis mapping assay.
exp_cml_cdh2_bcr_abl1_intersection
Map CDH2-GSK3β axis to BCR-ABL1 signaling: determine whether CDH2 upregulation suppresses BCR-ABL1-driven proliferation through MAPK/PI3K/JAK-STAT checkpoint effects, or through an off-axis Wnt/GSK3β-independent route. Mechanistically contextualize CDH2 effects within the documented CML pathophysiology nodes (Uncontrolled Myeloid Proliferation, Constitutive Tyrosine Kinase Activation, PI3K-AKT Pathway Activation, JAK-STAT Pathway Activation).
Model systems
K562 CML cell line
BCR-ABL1-positive cell line used to map the CDH2-GSK3β axis onto BCR-ABL1 downstream checkpoint signaling (MAPK/PI3K/JAK-STAT).
CELL LINE
Primary CML CD34+ progenitor culture
Patient-derived CD34+ progenitors used to confirm any BCR-ABL1 intersection observed in the K562 model in disease-relevant cells.
PRIMARY CELL CULTURE
Show evidence (1 reference)
PMID:42401590 SUPPORT In Vitro
"CDH2 overexpression suppressed proliferation, induced cell cycle arrest and early apoptosis. This was accompanied by increased total β-catenin protein but a reduced nuclear-to-cytoplasmic β-catenin ratio, without consistent changes in canonical Wnt target gene expression. Notably, the GSK3..."
This IN_VITRO evidence from K562 cells demonstrates CDH2-GSK3β-sensitive anti-proliferation but explicitly acknowledges mechanistic uncertainty and context-dependence across cancer types, indicating that human validation is required to interpret this as a generalizable CML mechanism rather than a K562 cell-line artifact.
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Pathophysiology

9
BCR-ABL1 Fusion Oncogene Formation
The t(9;22)(q34;q11) translocation juxtaposes the ABL1 tyrosine kinase gene on chromosome 9 with the BCR gene on chromosome 22, creating the Philadelphia chromosome. The resulting BCR-ABL1 fusion protein has constitutive tyrosine kinase activity independent of normal regulatory mechanisms.
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
protein phosphorylation GO:0006468 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves protein phosphorylation (GO:0006468). GO:0006468 is a biological process from the Gene Ontology.
Downstream
Constitutive Tyrosine Kinase Activation The BCR-ABL1 fusion protein exhibits ligand-independent kinase activity
Show evidence (2 references)
PMID:11287972 SUPPORT
"BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML."
This landmark paper establishes that BCR-ABL is a constitutively activated tyrosine kinase that causes CML, directly supporting the pathophysiology description.
CIVIC_ASSERTION:188 SUPPORT Other
"Chronic Myeloid Leukemia (CML) is a well-defined myeloproliferative neoplasm characterized by the t(9;22)(q34;q11.2) forming the BCR::ABL1 fusion."
CIViC's accepted diagnostic assertion supports the BCR::ABL1 fusion as the defining molecular event for CML.
Constitutive Tyrosine Kinase Activation
The BCR-ABL1 fusion protein exhibits constitutive tyrosine kinase activity, bypassing normal growth factor regulation. This activates multiple downstream signaling cascades including RAS-MAPK, PI3K-AKT, and JAK-STAT pathways, promoting cell proliferation and survival.
myeloid cell CL:0000763 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myeloid cell (CL:0000763). CL:0000763 is a cell type from the Cell Ontology.
protein tyrosine kinase activity GO:0018108 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein tyrosine kinase activity, annotated with peptidyl-tyrosine phosphorylation (GO:0018108). GO:0018108 is a biological process from the Gene Ontology. ↑ INCREASED signal transduction GO:0007165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased signal transduction (GO:0007165). GO:0007165 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
RAS-MAPK Pathway Hyperactivation BCR-ABL1 activates RAS via GRB2/SOS, driving the MAPK proliferative cascade
PI3K-AKT Pathway Activation BCR-ABL1 activates PI3K via direct binding and adaptor proteins
JAK-STAT Pathway Activation BCR-ABL1 activates JAK-STAT signaling independent of cytokine receptors
Reactive Oxygen Species Generation Constitutive kinase activity increases mitochondrial ROS production
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"Translation of the fusion products yields chimeric proteins of variable size that have increased tyrosine kinase activity."
The BCR-ABL1 chimeric fusion protein has constitutively increased tyrosine kinase activity, the defining lesion of this node.
RAS-MAPK Pathway Hyperactivation
BCR-ABL1 activates the RAS-MAPK signaling cascade through GRB2/SOS adaptor proteins. Constitutive MAPK pathway activation drives uncontrolled myeloid progenitor proliferation by upregulating cell cycle progression genes.
MAPK cascade GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Uncontrolled Myeloid Proliferation Hyperactive MAPK signaling drives excessive myeloid progenitor expansion
PI3K-AKT Pathway Activation
BCR-ABL1 activates the PI3K-AKT survival pathway through direct phosphorylation and adaptor protein recruitment. AKT phosphorylates and inactivates pro-apoptotic proteins (BAD, FOXO3a), upregulates BCL2 family anti-apoptotic members, and promotes cell survival.
PI3K-AKT signaling GO:0043491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased PI3K-AKT signaling, annotated with phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Apoptosis Resistance AKT-mediated inactivation of pro-apoptotic factors promotes leukemic cell survival
JAK-STAT Pathway Activation
BCR-ABL1 activates JAK-STAT signaling independently of cytokine receptor engagement. STAT5 activation drives expression of proliferative and anti-apoptotic target genes, contributing to cytokine-independent growth of leukemic cells.
JAK-STAT signaling GO:0007259 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased JAK-STAT signaling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Uncontrolled Myeloid Proliferation STAT5-driven transcriptional programs promote myeloid expansion
Apoptosis Resistance STAT5 upregulates BCL-XL and other anti-apoptotic factors
Reactive Oxygen Species Generation
BCR-ABL1 kinase activity increases mitochondrial reactive oxygen species (ROS) production. Chronic oxidative stress causes DNA double-strand breaks and impairs DNA repair fidelity, promoting acquisition of additional mutations and chromosomal abnormalities that drive disease progression.
reactive oxygen species biosynthetic process GO:1903409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased reactive oxygen species biosynthetic process (GO:1903409). GO:1903409 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Genomic Instability and Disease Progression ROS-induced DNA damage promotes acquisition of additional mutations driving blast crisis
Uncontrolled Myeloid Proliferation
BCR-ABL1 signaling drives excessive proliferation of myeloid progenitor cells, leading to marked expansion of the granulocytic lineage. The bone marrow becomes hypercellular with a massively expanded myeloid compartment.
granulocyte CL:0000094 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves granulocyte (CL:0000094). CL:0000094 is a cell type from the Cell Ontology. myeloid progenitor cell CL:0000049 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myeloid progenitor cell, annotated with common myeloid progenitor (CL:0000049). CL:0000049 is a cell type from the Cell Ontology.
myeloid cell homeostasis GO:0002262 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal myeloid cell homeostasis (GO:0002262). GO:0002262 is a biological process from the Gene Ontology. ⚠ ABNORMAL
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.
Apoptosis Resistance
BCR-ABL1 activates anti-apoptotic pathways, particularly through PI3K-AKT signaling and upregulation of BCL2 family members. This confers resistance to programmed cell death, allowing accumulation of leukemic cells.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology. ↓ DECREASED
Genomic Instability and Disease Progression
BCR-ABL1 induces genomic instability through reactive oxygen species generation and impaired DNA repair. This promotes acquisition of additional mutations and chromosomal abnormalities, driving progression from chronic phase to blast crisis.
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
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase"
Documents the natural-history progression from chronic phase to accelerated/blast crisis that this node captures.
✶

Histopathology

1
Philadelphia Chromosome Positive Neoplasm VERY_FREQUENT
CML is defined by the presence of the Philadelphia chromosome (BCR-ABL1 fusion).
Show evidence (1 reference)
PMID:33440869 SUPPORT
"CML is defined by the presence of the Philadelphia (Ph)"
Abstract defines CML by the Philadelphia chromosome.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chronic Myeloid Leukemia, BCR-ABL1 Positive Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Blood 4
Leukocytosis VERY_FREQUENT Increased total leukocyte count HP:0001974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukocytosis, annotated with Increased total leukocyte count (HP:0001974). HP:0001974 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26646444 SUPPORT Human Clinical
"Markedly increased leukocyte count and a higher incidence of splenomegaly are characteristic features at diagnosis"
This review identifies a markedly increased leukocyte count as a characteristic feature of CML at diagnosis.
Basophilia VERY_FREQUENT Increased total basophil count HP:0031807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basophilia, annotated with Increased total basophil count (HP:0031807). HP:0031807 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36611797 SUPPORT Human Clinical
"Basophilia is a crucial prognostic variable in Ph-chromosome-positive chronic myeloid leukemia (CML)."
This study of CML patients establishes basophilia as a characteristic and prognostically important feature of Ph-positive CML.
Thrombocytosis FREQUENT HP:0001894 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytosis (HP:0001894). HP:0001894 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34824846 SUPPORT Human Clinical
"anemia, basophilia, eosinophilia, thrombocytosis and hyperleukocytosis were detected. The patient was subsequently diagnosed with chronic myeloid leukemia."
This case documents thrombocytosis as part of the presenting blood-count abnormalities leading to a CML diagnosis.
Anemia FREQUENT 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.
Show evidence (1 reference)
PMID:34824846 SUPPORT Human Clinical
"anemia, basophilia, eosinophilia, thrombocytosis and hyperleukocytosis were detected. The patient was subsequently diagnosed with chronic myeloid leukemia."
This case documents anemia among the presenting blood-count abnormalities leading to a CML diagnosis.
Cardiovascular 1
Splenomegaly VERY_FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34248591 SUPPORT Human Clinical
"Physical examination showed hepatomegaly and splenomegaly."
This case of Philadelphia-positive CML documents splenomegaly on physical examination.
PMID:26646444 SUPPORT Human Clinical
"Markedly increased leukocyte count and a higher incidence of splenomegaly are characteristic features at diagnosis"
This review identifies splenomegaly as a characteristic feature of CML at diagnosis.
Digestive 1
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34248591 SUPPORT Human Clinical
"Physical examination showed hepatomegaly and splenomegaly."
This case of Philadelphia-positive CML documents hepatomegaly on physical examination.
Constitutional 1
Fatigue VERY_FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23179489 SUPPORT Human Clinical
"CML patients (n = 62) taking a TKI (imatinib 55 %, nilotinib 31 %, and dasatinib 14 %) reported significantly worse fatigue severity (p < .001), fatigue interference (p < .001)"
This controlled comparison shows CML patients experience significantly worse fatigue than matched cancer-free controls.
🧬

Genetic Associations

1
BCR-ABL1 (Somatic Fusion Oncogene)
Show evidence (3 references)
PMID:11287972 SUPPORT
"BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML)."
Establishes that BCR-ABL fusion is the causative genetic lesion in CML.
PMID:11423618 SUPPORT
"These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event."
Confirms oncogene addiction - CML cells remain dependent on BCR-ABL signaling even in advanced disease.
CIVIC_ASSERTION:188 SUPPORT Other
"BCR::ABL1 fusion is a diagnostic criterion for Chronic Myeloid Leukemia (CML)."
CIViC's accepted assertion supports BCR::ABL1 as the defining genetic alteration for this CML entry.
🗃️

External Assertions

3
CIViC BCR::ABL1 diagnostic assertion
CIViC accepted assertion CIVIC_ASSERTION:188
CIViC accepted assertion that BCR::ABL1 fusion is a diagnostic marker for chronic myeloid leukemia.
01-May-2026 CIViC accepted assertion: molecular_profile="BCR::ABL1 Fusion"; disease="Chronic Myeloid Leukemia"; assertion_type=Diagnostic; significance=Positive; AMP category=Tier I - Level A.
Show evidence (1 reference)
CIVIC_ASSERTION:188 SUPPORT Other
"BCR::ABL1 fusion is a diagnostic criterion for Chronic Myeloid Leukemia (CML)."
CIViC records an accepted diagnostic assertion for BCR::ABL1 fusion in chronic myeloid leukemia.
CIViC BCR::ABL1 imatinib sensitivity evidence item
CIViC accepted evidence item CIVIC_EID:260
CIViC accepted evidence item linking BCR::ABL1 fusion in chronic myeloid leukemia to imatinib sensitivity/response.
01-May-2026 CIViC accepted evidence item: evidence_type=Predictive; evidence_level=A; significance=Sensitivity/Response; therapy=Imatinib; citation_id=PMID:20537386.
Show evidence (1 reference)
CIVIC_EID:260 SUPPORT Other
"The clinical use of imatinib in patients with BCR-ABL fusion has resulted in drastic prognostic improvements in patients with CML."
CIViC records an accepted predictive sensitivity evidence item for BCR::ABL1 fusion and imatinib in CML.
CIViC BCR::ABL1 plus ABL1 T315I imatinib resistance evidence item
CIViC accepted evidence item CIVIC_EID:234
CIViC accepted evidence item linking BCR::ABL1 fusion with ABL1 T315I in chronic myeloid leukemia to imatinib resistance.
01-May-2026 CIViC accepted evidence item: molecular_profile="BCR::ABL1 Fusion AND ABL1 T315I"; evidence_type=Predictive; evidence_level=B; significance=Resistance; therapy=Imatinib; citation_id=PMID:20537386.
Show evidence (1 reference)
CIVIC_EID:234 SUPPORT Other
"In chronic myeloid leukemia patients with the ABL T315I mutation, tumors have shown to be resistant to imatinib treatment."
CIViC records an accepted predictive resistance evidence item for ABL1 T315I and imatinib in CML.
💊

Medical Actions

5
Imatinib
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: imatinib CHEBI:45783 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses imatinib (CHEBI:45783). CHEBI:45783 is a therapeutic agent from Chemical Entities of Biological Interest.
First-generation tyrosine kinase inhibitor that revolutionized CML treatment. Competitively inhibits BCR-ABL1 ATP binding, inducing molecular remission in most chronic phase patients. Standard first-line therapy with excellent long-term outcomes.
Mechanism Target:
INHIBITS Constitutive Tyrosine Kinase Activation — Imatinib is an ATP-competitive inhibitor of the BCR-ABL1 tyrosine kinase, abrogating its constitutive kinase activity and the downstream proliferative signaling.
Show evidence (1 reference)
PMID:11287972 SUPPORT Human Clinical
"Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML."
Imatinib was designed as a specific inhibitor of BCR-ABL tyrosine kinase activity, directly supporting the mechanism by which it inhibits the constitutive kinase-activation node.
🔬 3D Structures:
1IEP X-ray 2.1 Å ⚗️ imatinib
ABL kinase domain in complex with imatinib (STI-571), the landmark structure showing how imatinib binds the inactive DFG-out conformation and blocks ATP access
Show evidence (3 references)
PMID:11287972 SUPPORT
"Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy."
The Druker phase 1 trial demonstrated that imatinib (STI571) induced complete hematologic responses in the vast majority of chronic phase CML patients.
PMID:11287972 SUPPORT
"Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer."
This establishes that imatinib's efficacy proves the oncogene addiction paradigm in CML.
CIVIC_EID:260 SUPPORT Other
"The clinical use of imatinib in patients with BCR-ABL fusion has resulted in drastic prognostic improvements in patients with CML."
CIViC's accepted evidence item directly supports imatinib sensitivity/response in BCR::ABL1-positive CML.
Dasatinib
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: dasatinib CHEBI:49375 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dasatinib, annotated with dasatinib (anhydrous) (CHEBI:49375). CHEBI:49375 is a therapeutic agent from Chemical Entities of Biological Interest.
Second-generation TKI with greater potency against BCR-ABL1 and activity against many imatinib-resistant mutations. Also inhibits SRC family kinases. Used for imatinib intolerance/resistance or as first-line therapy.
Mechanism Target:
INHIBITS Constitutive Tyrosine Kinase Activation — Dasatinib is a second-generation BCR-ABL1 (and SRC-family) tyrosine kinase inhibitor that blocks constitutive kinase activity, active against most imatinib-resistant mutations except T315I.
Show evidence (1 reference)
PMID:20525995 SUPPORT Human Clinical
"The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001)"
The DASISION randomized trial showed dasatinib produced faster, deeper molecular and cytogenetic responses than imatinib in newly diagnosed chronic-phase CML, supporting its use as first-line/second-generation TKI.
Nilotinib
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: nilotinib CHEBI:52172 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses nilotinib (CHEBI:52172). CHEBI:52172 is a therapeutic agent from Chemical Entities of Biological Interest.
Second-generation TKI designed for improved BCR-ABL1 binding. More selective than dasatinib with different side effect profile. Used for imatinib intolerance/resistance or first-line therapy.
Mechanism Target:
INHIBITS Constitutive Tyrosine Kinase Activation — Nilotinib is a second-generation, high-affinity BCR-ABL1 tyrosine kinase inhibitor that suppresses constitutive kinase activity.
Show evidence (1 reference)
PMID:20525993 SUPPORT Human Clinical
"At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons)."
The ENESTnd randomized trial showed nilotinib nearly doubled the 12-month major molecular response rate versus imatinib in newly diagnosed CML, supporting its use as a first-line second-generation TKI.
Ponatinib
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: ponatinib CHEBI:78543 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ponatinib (CHEBI:78543). CHEBI:78543 is a therapeutic agent from Chemical Entities of Biological Interest.
Third-generation TKI active against the T315I gatekeeper mutation that confers resistance to other TKIs. Reserved for patients with T315I mutation or failure of multiple prior TKIs due to cardiovascular risks.
Mechanism Target:
INHIBITS Constitutive Tyrosine Kinase Activation — Ponatinib is a third-generation BCR-ABL1 inhibitor active against the T315I gatekeeper mutation, blocking constitutive kinase activity.
🔬 3D Structures:
3OXZ X-ray 1.8 Å ⚗️ ponatinib
Ponatinib bound to native ABL1 kinase domain, showing how the linear ethynyl linker avoids the T315I steric clash that blocks imatinib binding at the gatekeeper residue
1IEP X-ray 2.1 Å ⚗️ imatinib
Imatinib/ABL1 co-crystal — T315 forms a hydrogen bond with imatinib that is lost upon T315I mutation, explaining gatekeeper resistance
Show evidence (2 references)
PMID:11423618 SUPPORT
"In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance."
This paper identified the T315I gatekeeper mutation that confers resistance to first and second-generation TKIs, establishing the need for third-generation TKIs like ponatinib.
CIVIC_EID:234 SUPPORT Other
"In chronic myeloid leukemia patients with the ABL T315I mutation, tumors have shown to be resistant to imatinib treatment."
CIViC's accepted evidence item supports T315I as an imatinib-resistance marker, which is the rationale for T315I-active later-generation TKIs such as ponatinib.
Allogeneic Stem Cell Transplantation
Action: Allogeneic Stem Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Allogeneic Stem Cell Transplantation (NCIT:C201466). NCIT:C201466 is a clinical intervention from the NCI Thesaurus. NCIT:C201466
Potentially curative option historically used as primary therapy before TKI era. Now reserved for patients failing multiple TKIs, those with T315I mutation without ponatinib access, or blast crisis. Significant morbidity and mortality risks.
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"allogeneic stem-cell transplantation has provided the groundwork for a cure of chronic myelogenous leukemia"
This review documents allogeneic stem-cell transplantation as the established potentially curative therapy for CML.
🔬

Biochemical Markers

2
Philadelphia Chromosome Detection
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"this translocation leads to a shortened chromosome 22, called the Philadelphia chromosome"
This review describes the t(9;22) translocation producing the shortened chromosome 22 (Philadelphia chromosome) detected in CML.
BCR-ABL1 Fusion Transcript
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"most patients with chronic myelogenous leukemia demonstrate BCR-ABL fusion genes in hematopoietic progenitor cells, which result from a reciprocal translocation between chromosomes 9 and 22"
This review documents the BCR-ABL fusion gene as the defining molecular lesion of CML that is detected as a diagnostic marker.
🪜

Stages

3
Chronic Phase
Initial indolent phase characterized by mature granulocyte expansion with less than 10% blasts in blood or bone marrow. Most patients are diagnosed in this phase and respond well to tyrosine kinase inhibitors.
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"It is characterized by a biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase."
This review defines CML's triphasic clinical course beginning with the indolent (benign) chronic phase in which most patients are diagnosed.
Accelerated Phase
Transitional phase marked by increasing blast counts (10-19%), basophilia, thrombocytopenia or thrombocytosis, and additional cytogenetic abnormalities. Indicates disease progression and decreased TKI responsiveness.
Show evidence (1 reference)
PMID:10428738 SUPPORT Human Clinical
"It is characterized by a biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase."
This review defines the accelerated phase as the transitional stage in the triphasic CML course between chronic phase and blast crisis.
Blast Crisis
Terminal phase resembling acute leukemia with 20% or more blasts in blood or bone marrow. May be myeloid or lymphoid lineage. Poor prognosis with limited treatment options.
Show evidence (1 reference)
PMID:11423618 SUPPORT
"Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse."
This paper demonstrates that advanced phase CML (blast crisis) has poor outcomes even with TKI therapy, reflecting disease progression.
{ }

Source YAML

click to show 
name: Chronic Myeloid Leukemia, BCR-ABL1 Positive
creation_date: '2026-01-26T02:55:13Z'
description: >-
  Chronic myeloid leukemia (CML), BCR-ABL1 positive, is a myeloproliferative neoplasm
  characterized by the Philadelphia chromosome, resulting from a reciprocal translocation
  t(9;22)(q34;q11) that creates the BCR-ABL1 fusion gene. The constitutively active
  BCR-ABL1 tyrosine kinase drives uncontrolled myeloid cell proliferation. CML is the
  paradigmatic example of oncogene addiction and targeted therapy success, with tyrosine
  kinase inhibitors transforming it from a fatal disease to a manageable chronic condition.
  This entry covers BCR-ABL1 positive CML, which represents approximately 95% of all CML cases.
categories:
- Hematologic Malignancy
- Myeloproliferative Neoplasm
parents:
- myeloid leukemia
external_assertions:
- name: CIViC BCR::ABL1 diagnostic assertion
  source: CIViC
  assertion_type: accepted_assertion
  external_id: CIVIC_ASSERTION:188
  url: https://civicdb.org/links/assertions/188
  description: >-
    CIViC accepted assertion that BCR::ABL1 fusion is a diagnostic marker for
    chronic myeloid leukemia.
  notes: >-
    01-May-2026 CIViC accepted assertion: molecular_profile="BCR::ABL1
    Fusion"; disease="Chronic Myeloid Leukemia"; assertion_type=Diagnostic;
    significance=Positive; AMP category=Tier I - Level A.
  evidence:
  - reference: CIVIC_ASSERTION:188
    reference_title: "BCR::ABL1 Fusion / Chronic Myeloid Leukemia (Diagnostic Positive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: BCR::ABL1 fusion is a diagnostic criterion for Chronic Myeloid Leukemia (CML).
    explanation: CIViC records an accepted diagnostic assertion for BCR::ABL1 fusion in chronic myeloid leukemia.
- name: CIViC BCR::ABL1 imatinib sensitivity evidence item
  source: CIViC
  assertion_type: accepted_evidence_item
  external_id: CIVIC_EID:260
  url: https://civicdb.org/links/evidence_items/260
  description: >-
    CIViC accepted evidence item linking BCR::ABL1 fusion in chronic myeloid
    leukemia to imatinib sensitivity/response.
  notes: >-
    01-May-2026 CIViC accepted evidence item: evidence_type=Predictive;
    evidence_level=A; significance=Sensitivity/Response; therapy=Imatinib;
    citation_id=PMID:20537386.
  evidence:
  - reference: CIVIC_EID:260
    reference_title: "BCR::ABL1 Fusion / Chronic Myeloid Leukemia (Predictive Sensitivity/Response)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The clinical use of imatinib in patients with BCR-ABL fusion has resulted in drastic prognostic improvements in patients with CML.
    explanation: CIViC records an accepted predictive sensitivity evidence item for BCR::ABL1 fusion and imatinib in CML.
- name: CIViC BCR::ABL1 plus ABL1 T315I imatinib resistance evidence item
  source: CIViC
  assertion_type: accepted_evidence_item
  external_id: CIVIC_EID:234
  url: https://civicdb.org/links/evidence_items/234
  description: >-
    CIViC accepted evidence item linking BCR::ABL1 fusion with ABL1 T315I in
    chronic myeloid leukemia to imatinib resistance.
  notes: >-
    01-May-2026 CIViC accepted evidence item: molecular_profile="BCR::ABL1
    Fusion AND ABL1 T315I"; evidence_type=Predictive; evidence_level=B;
    significance=Resistance; therapy=Imatinib; citation_id=PMID:20537386.
  evidence:
  - reference: CIVIC_EID:234
    reference_title: "BCR::ABL1 Fusion AND ABL1 T315I / Chronic Myeloid Leukemia (Predictive Resistance)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In chronic myeloid leukemia patients with the ABL T315I mutation, tumors have shown to be resistant to imatinib treatment.
    explanation: CIViC records an accepted predictive resistance evidence item for ABL1 T315I and imatinib in CML.
stages:
- name: Chronic Phase
  description: >-
    Initial indolent phase characterized by mature granulocyte expansion with
    less than 10% blasts in blood or bone marrow. Most patients are diagnosed
    in this phase and respond well to tyrosine kinase inhibitors.
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by a biphasic or triphasic clinical course in which a
      benign chronic phase is followed by transformation into an accelerated and
      blastic phase.
    explanation: >-
      This review defines CML's triphasic clinical course beginning with the
      indolent (benign) chronic phase in which most patients are diagnosed.
- name: Accelerated Phase
  description: >-
    Transitional phase marked by increasing blast counts (10-19%), basophilia,
    thrombocytopenia or thrombocytosis, and additional cytogenetic abnormalities.
    Indicates disease progression and decreased TKI responsiveness.
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is characterized by a biphasic or triphasic clinical course in which a
      benign chronic phase is followed by transformation into an accelerated and
      blastic phase.
    explanation: >-
      This review defines the accelerated phase as the transitional stage in the
      triphasic CML course between chronic phase and blast crisis.
- name: Blast Crisis
  description: >-
    Terminal phase resembling acute leukemia with 20% or more blasts in blood
    or bone marrow. May be myeloid or lymphoid lineage. Poor prognosis with
    limited treatment options.
  evidence:
  - reference: PMID:11423618
    reference_title: "Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification."
    supports: SUPPORT
    snippet: "Clinical studies with the Abl tyrosine kinase inhibitor STI-571 in chronic myeloid leukemia demonstrate that many patients with advanced stage disease respond initially but then relapse."
    explanation: This paper demonstrates that advanced phase CML (blast crisis) has poor outcomes even with TKI therapy, reflecting disease progression.
pathophysiology:
- name: BCR-ABL1 Fusion Oncogene Formation
  conforms_to: "sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion"
  description: >-
    The t(9;22)(q34;q11) translocation juxtaposes the ABL1 tyrosine kinase gene
    on chromosome 9 with the BCR gene on chromosome 22, creating the Philadelphia
    chromosome. The resulting BCR-ABL1 fusion protein has constitutive tyrosine
    kinase activity independent of normal regulatory mechanisms.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: protein phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
  gene_products:
  - preferred_term: BCR-ABL1 fusion protein
    term:
      id: NCIT:C16325
      label: BCR/ABL1 Fusion Protein
  downstream:
  - target: Constitutive Tyrosine Kinase Activation
    description: The BCR-ABL1 fusion protein exhibits ligand-independent kinase activity
  evidence:
  - reference: PMID:11287972
    reference_title: "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia."
    supports: SUPPORT
    snippet: "BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML."
    explanation: This landmark paper establishes that BCR-ABL is a constitutively activated tyrosine kinase that causes CML, directly supporting the pathophysiology description.
  - reference: CIVIC_ASSERTION:188
    reference_title: "BCR::ABL1 Fusion / Chronic Myeloid Leukemia (Diagnostic Positive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Chronic Myeloid Leukemia (CML) is a well-defined myeloproliferative neoplasm characterized by the t(9;22)(q34;q11.2) forming the BCR::ABL1 fusion.
    explanation: CIViC's accepted diagnostic assertion supports the BCR::ABL1 fusion as the defining molecular event for CML.
- name: Constitutive Tyrosine Kinase Activation
  description: >-
    The BCR-ABL1 fusion protein exhibits constitutive tyrosine kinase activity,
    bypassing normal growth factor regulation. This activates multiple downstream
    signaling cascades including RAS-MAPK, PI3K-AKT, and JAK-STAT pathways,
    promoting cell proliferation and survival.
  cell_types:
  - preferred_term: myeloid cell
    term:
      id: CL:0000763
      label: myeloid cell
  biological_processes:
  - preferred_term: protein tyrosine kinase activity
    modifier: INCREASED
    term:
      id: GO:0018108
      label: peptidyl-tyrosine phosphorylation
  - preferred_term: signal transduction
    modifier: INCREASED
    term:
      id: GO:0007165
      label: signal transduction
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Translation of the fusion products yields chimeric proteins of variable size that have increased tyrosine kinase activity."
    explanation: The BCR-ABL1 chimeric fusion protein has constitutively increased tyrosine kinase activity, the defining lesion of this node.
  downstream:
  - target: RAS-MAPK Pathway Hyperactivation
    description: BCR-ABL1 activates RAS via GRB2/SOS, driving the MAPK proliferative cascade
  - target: PI3K-AKT Pathway Activation
    description: BCR-ABL1 activates PI3K via direct binding and adaptor proteins
  - target: JAK-STAT Pathway Activation
    description: BCR-ABL1 activates JAK-STAT signaling independent of cytokine receptors
  - target: Reactive Oxygen Species Generation
    description: Constitutive kinase activity increases mitochondrial ROS production
- name: RAS-MAPK Pathway Hyperactivation
  conforms_to: "sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation"
  description: >-
    BCR-ABL1 activates the RAS-MAPK signaling cascade through GRB2/SOS adaptor
    proteins. Constitutive MAPK pathway activation drives uncontrolled myeloid
    progenitor proliferation by upregulating cell cycle progression genes.
  biological_processes:
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  downstream:
  - target: Uncontrolled Myeloid Proliferation
    description: Hyperactive MAPK signaling drives excessive myeloid progenitor expansion
- name: PI3K-AKT Pathway Activation
  description: >-
    BCR-ABL1 activates the PI3K-AKT survival pathway through direct phosphorylation
    and adaptor protein recruitment. AKT phosphorylates and inactivates pro-apoptotic
    proteins (BAD, FOXO3a), upregulates BCL2 family anti-apoptotic members, and
    promotes cell survival.
  biological_processes:
  - preferred_term: PI3K-AKT signaling
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  downstream:
  - target: Apoptosis Resistance
    description: AKT-mediated inactivation of pro-apoptotic factors promotes leukemic cell survival
- name: JAK-STAT Pathway Activation
  description: >-
    BCR-ABL1 activates JAK-STAT signaling independently of cytokine receptor
    engagement. STAT5 activation drives expression of proliferative and
    anti-apoptotic target genes, contributing to cytokine-independent growth
    of leukemic cells.
  biological_processes:
  - preferred_term: JAK-STAT signaling
    modifier: INCREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  downstream:
  - target: Uncontrolled Myeloid Proliferation
    description: STAT5-driven transcriptional programs promote myeloid expansion
  - target: Apoptosis Resistance
    description: STAT5 upregulates BCL-XL and other anti-apoptotic factors
- name: Reactive Oxygen Species Generation
  description: >-
    BCR-ABL1 kinase activity increases mitochondrial reactive oxygen species (ROS)
    production. Chronic oxidative stress causes DNA double-strand breaks and
    impairs DNA repair fidelity, promoting acquisition of additional mutations
    and chromosomal abnormalities that drive disease progression.
  biological_processes:
  - preferred_term: reactive oxygen species biosynthetic process
    modifier: INCREASED
    term:
      id: GO:1903409
      label: reactive oxygen species biosynthetic process
  downstream:
  - target: Genomic Instability and Disease Progression
    description: ROS-induced DNA damage promotes acquisition of additional mutations driving blast crisis
- name: Uncontrolled Myeloid Proliferation
  conforms_to: "sustaining_proliferative_signaling#Growth-Factor-Independent Proliferation"
  description: >-
    BCR-ABL1 signaling drives excessive proliferation of myeloid progenitor cells,
    leading to marked expansion of the granulocytic lineage. The bone marrow becomes
    hypercellular with a massively expanded myeloid compartment.
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  cell_types:
  - preferred_term: granulocyte
    term:
      id: CL:0000094
      label: granulocyte
  - preferred_term: myeloid progenitor cell
    term:
      id: CL:0000049
      label: common myeloid progenitor
  biological_processes:
  - preferred_term: myeloid cell homeostasis
    modifier: ABNORMAL
    term:
      id: GO:0002262
      label: myeloid cell homeostasis
- name: Apoptosis Resistance
  description: >-
    BCR-ABL1 activates anti-apoptotic pathways, particularly through PI3K-AKT
    signaling and upregulation of BCL2 family members. This confers resistance
    to programmed cell death, allowing accumulation of leukemic cells.
  biological_processes:
  - preferred_term: apoptotic process
    modifier: DECREASED
    term:
      id: GO:0006915
      label: apoptotic process
- name: Genomic Instability and Disease Progression
  description: >-
    BCR-ABL1 induces genomic instability through reactive oxygen species generation
    and impaired DNA repair. This promotes acquisition of additional mutations and
    chromosomal abnormalities, driving progression from chronic phase to blast crisis.
  biological_processes:
  - preferred_term: DNA repair
    modifier: DECREASED
    term:
      id: GO:0006281
      label: DNA repair
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biphasic or triphasic clinical course in which a benign chronic phase is followed by transformation into an accelerated and blastic phase"
    explanation: Documents the natural-history progression from chronic phase to accelerated/blast crisis that this node captures.
histopathology:
- name: Philadelphia Chromosome Positive Neoplasm
  finding_term:
    preferred_term: Chronic Myeloid Leukemia, BCR-ABL1 Positive
    term:
      id: NCIT:C3174
      label: Chronic Myeloid Leukemia, BCR-ABL1 Positive
  frequency: VERY_FREQUENT
  description: CML is defined by the presence of the Philadelphia chromosome (BCR-ABL1 fusion).
  evidence:
  - reference: PMID:33440869
    reference_title: "Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms."
    supports: SUPPORT
    snippet: "CML is defined by the presence of the Philadelphia (Ph)"
    explanation: Abstract defines CML by the Philadelphia chromosome.

phenotypes:
- category: Hematologic
  name: Leukocytosis
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Marked elevation of white blood cell count, often exceeding 100,000/μL at diagnosis.
    The differential shows increased granulocytes at all stages of maturation with
    a left shift to myelocytes and metamyelocytes.
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:26646444
    reference_title: "Optimal management for pediatric chronic myeloid leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Markedly increased leukocyte count and a higher incidence of splenomegaly
      are characteristic features at diagnosis
    explanation: >-
      This review identifies a markedly increased leukocyte count as a
      characteristic feature of CML at diagnosis.
- category: Hematologic
  name: Basophilia
  frequency: VERY_FREQUENT
  description: >-
    Elevated basophil count is characteristic of CML and may indicate disease
    acceleration when markedly increased.
  phenotype_term:
    preferred_term: Basophilia
    term:
      id: HP:0031807
      label: Increased total basophil count
  evidence:
  - reference: PMID:36611797
    reference_title: "Identification of CD203c as a New Basophil-Specific Flow-Marker in Ph(+) Chronic Myeloid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Basophilia is a crucial prognostic variable in Ph-chromosome-positive
      chronic myeloid leukemia (CML).
    explanation: >-
      This study of CML patients establishes basophilia as a characteristic and
      prognostically important feature of Ph-positive CML.
- category: Hematologic
  name: Thrombocytosis
  frequency: FREQUENT
  description: >-
    Elevated platelet count occurs in many patients and may precede diagnosis.
    Extreme thrombocytosis can occur in some cases.
  phenotype_term:
    preferred_term: Thrombocytosis
    term:
      id: HP:0001894
      label: Thrombocytosis
  evidence:
  - reference: PMID:34824846
    reference_title: "Priapism as the first manifestation in chronic myeloid leukemia: A case report and focused review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anemia, basophilia, eosinophilia, thrombocytosis and hyperleukocytosis
      were detected. The patient was subsequently diagnosed with chronic myeloid
      leukemia.
    explanation: >-
      This case documents thrombocytosis as part of the presenting blood-count
      abnormalities leading to a CML diagnosis.
- category: Hematologic
  name: Anemia
  frequency: FREQUENT
  description: >-
    Normochromic normocytic anemia develops due to bone marrow replacement by
    leukemic cells and ineffective erythropoiesis.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:34824846
    reference_title: "Priapism as the first manifestation in chronic myeloid leukemia: A case report and focused review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anemia, basophilia, eosinophilia, thrombocytosis and hyperleukocytosis
      were detected. The patient was subsequently diagnosed with chronic myeloid
      leukemia.
    explanation: >-
      This case documents anemia among the presenting blood-count abnormalities
      leading to a CML diagnosis.
- category: Constitutional
  name: Fatigue
  frequency: VERY_FREQUENT
  description: >-
    Profound fatigue is common, related to anemia and hypermetabolic state from
    rapid cell turnover.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:23179489
    reference_title: "Quality of life outcomes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a controlled comparison."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CML patients (n = 62) taking a TKI (imatinib 55 %, nilotinib 31 %, and
      dasatinib 14 %) reported significantly worse fatigue severity (p < .001),
      fatigue interference (p < .001)
    explanation: >-
      This controlled comparison shows CML patients experience significantly
      worse fatigue than matched cancer-free controls.
- category: Abdominal
  name: Splenomegaly
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Massive splenomegaly from extramedullary hematopoiesis is characteristic.
    The spleen may extend to the pelvis and cause abdominal discomfort, early
    satiety, and left upper quadrant pain.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:34248591
    reference_title: "Bilateral Serous Retinal Detachment in Lymphoid Blast Crisis of Chronic Myeloid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Physical examination showed hepatomegaly and splenomegaly.
    explanation: >-
      This case of Philadelphia-positive CML documents splenomegaly on physical
      examination.
  - reference: PMID:26646444
    reference_title: "Optimal management for pediatric chronic myeloid leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Markedly increased leukocyte count and a higher incidence of splenomegaly
      are characteristic features at diagnosis
    explanation: >-
      This review identifies splenomegaly as a characteristic feature of CML at
      diagnosis.
- category: Abdominal
  name: Hepatomegaly
  frequency: FREQUENT
  description: >-
    Liver enlargement from extramedullary hematopoiesis and leukemic infiltration.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:34248591
    reference_title: "Bilateral Serous Retinal Detachment in Lymphoid Blast Crisis of Chronic Myeloid Leukemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Physical examination showed hepatomegaly and splenomegaly.
    explanation: >-
      This case of Philadelphia-positive CML documents hepatomegaly on physical
      examination.
biochemical:
- name: Philadelphia Chromosome Detection
  notes: >-
    Cytogenetic analysis reveals t(9;22)(q34;q11) translocation creating the
    Philadelphia chromosome in 95% of CML cases.
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this translocation leads to a shortened chromosome 22, called the
      Philadelphia chromosome
    explanation: >-
      This review describes the t(9;22) translocation producing the shortened
      chromosome 22 (Philadelphia chromosome) detected in CML.
- name: BCR-ABL1 Fusion Transcript
  biomarker_term:
    preferred_term: BCR-ABL1 fusion protein
    term:
      id: NCIT:C36715
      label: BCR-ABL1 Fusion Protein Expression
  notes: >-
    RT-PCR or FISH detection of BCR-ABL1 fusion is diagnostic and used for
    monitoring molecular response to therapy.
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most patients with chronic myelogenous leukemia demonstrate BCR-ABL fusion
      genes in hematopoietic progenitor cells, which result from a reciprocal
      translocation between chromosomes 9 and 22
    explanation: >-
      This review documents the BCR-ABL fusion gene as the defining molecular
      lesion of CML that is detected as a diagnostic marker.
genetic:
- name: BCR-ABL1
  association: Somatic Fusion Oncogene
  notes: >-
    The t(9;22)(q34;q11) translocation creates a fusion between BCR on chromosome 22
    and ABL1 on chromosome 9. The resulting BCR-ABL1 fusion protein (p210 in CML)
    has constitutive tyrosine kinase activity that drives the disease.
  evidence:
  - reference: PMID:11287972
    reference_title: "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia."
    supports: SUPPORT
    snippet: "BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML)."
    explanation: Establishes that BCR-ABL fusion is the causative genetic lesion in CML.
  - reference: PMID:11423618
    reference_title: "Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification."
    supports: SUPPORT
    snippet: "These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event."
    explanation: Confirms oncogene addiction - CML cells remain dependent on BCR-ABL signaling even in advanced disease.
  - reference: CIVIC_ASSERTION:188
    reference_title: "BCR::ABL1 Fusion / Chronic Myeloid Leukemia (Diagnostic Positive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: BCR::ABL1 fusion is a diagnostic criterion for Chronic Myeloid Leukemia (CML).
    explanation: CIViC's accepted assertion supports BCR::ABL1 as the defining genetic alteration for this CML entry.
treatments:
- name: Imatinib
  target_mechanisms:
  - target: Constitutive Tyrosine Kinase Activation
    treatment_effect: INHIBITS
    description: Imatinib is an ATP-competitive inhibitor of the BCR-ABL1 tyrosine kinase, abrogating its constitutive kinase activity and the downstream proliferative signaling.
    evidence:
    - reference: PMID:11287972
      reference_title: "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Since tyrosine kinase activity is essential to the transforming function
        of BCR-ABL, an inhibitor of the kinase could be an effective treatment for
        CML.
      explanation: >-
        Imatinib was designed as a specific inhibitor of BCR-ABL tyrosine kinase
        activity, directly supporting the mechanism by which it inhibits the
        constitutive kinase-activation node.
  description: >-
    First-generation tyrosine kinase inhibitor that revolutionized CML treatment.
    Competitively inhibits BCR-ABL1 ATP binding, inducing molecular remission in
    most chronic phase patients. Standard first-line therapy with excellent long-term outcomes.
  pdb_structures:
  - pdb_id: 1IEP
    description: ABL kinase domain in complex with imatinib (STI-571), the landmark structure showing how imatinib binds the inactive DFG-out conformation and blocks ATP access
    resolution_angstrom: 2.1
    method: X-ray
    ligand: imatinib
    target_protein: ABL1 kinase domain
    publication: PMID:11134073
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: imatinib
      term:
        id: CHEBI:45783
        label: imatinib
  evidence:
  - reference: PMID:11287972
    reference_title: "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia."
    supports: SUPPORT
    snippet: "Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy."
    explanation: The Druker phase 1 trial demonstrated that imatinib (STI571) induced complete hematologic responses in the vast majority of chronic phase CML patients.
  - reference: PMID:11287972
    reference_title: "Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia."
    supports: SUPPORT
    snippet: "Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer."
    explanation: This establishes that imatinib's efficacy proves the oncogene addiction paradigm in CML.
  - reference: CIVIC_EID:260
    reference_title: "BCR::ABL1 Fusion / Chronic Myeloid Leukemia (Predictive Sensitivity/Response)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The clinical use of imatinib in patients with BCR-ABL fusion has resulted in drastic prognostic improvements in patients with CML.
    explanation: CIViC's accepted evidence item directly supports imatinib sensitivity/response in BCR::ABL1-positive CML.
- name: Dasatinib
  target_mechanisms:
  - target: Constitutive Tyrosine Kinase Activation
    treatment_effect: INHIBITS
    description: Dasatinib is a second-generation BCR-ABL1 (and SRC-family) tyrosine kinase inhibitor that blocks constitutive kinase activity, active against most imatinib-resistant mutations except T315I.
  description: >-
    Second-generation TKI with greater potency against BCR-ABL1 and activity against
    many imatinib-resistant mutations. Also inhibits SRC family kinases. Used for
    imatinib intolerance/resistance or as first-line therapy.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: dasatinib
      term:
        id: CHEBI:49375
        label: dasatinib (anhydrous)
  evidence:
  - reference: PMID:20525995
    reference_title: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rate of major molecular response was higher with dasatinib than with
      imatinib (46% vs. 28%, P<0.0001)
    explanation: >-
      The DASISION randomized trial showed dasatinib produced faster, deeper
      molecular and cytogenetic responses than imatinib in newly diagnosed
      chronic-phase CML, supporting its use as first-line/second-generation TKI.
- name: Nilotinib
  target_mechanisms:
  - target: Constitutive Tyrosine Kinase Activation
    treatment_effect: INHIBITS
    description: Nilotinib is a second-generation, high-affinity BCR-ABL1 tyrosine kinase inhibitor that suppresses constitutive kinase activity.
  description: >-
    Second-generation TKI designed for improved BCR-ABL1 binding. More selective
    than dasatinib with different side effect profile. Used for imatinib
    intolerance/resistance or first-line therapy.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: nilotinib
      term:
        id: CHEBI:52172
        label: nilotinib
  evidence:
  - reference: PMID:20525993
    reference_title: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 12 months, the rates of major molecular response for nilotinib (44% for
      the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for
      imatinib (22%) (P<0.001 for both comparisons).
    explanation: >-
      The ENESTnd randomized trial showed nilotinib nearly doubled the 12-month
      major molecular response rate versus imatinib in newly diagnosed CML,
      supporting its use as a first-line second-generation TKI.
- name: Ponatinib
  target_mechanisms:
  - target: Constitutive Tyrosine Kinase Activation
    treatment_effect: INHIBITS
    description: Ponatinib is a third-generation BCR-ABL1 inhibitor active against the T315I gatekeeper mutation, blocking constitutive kinase activity.
  description: >-
    Third-generation TKI active against the T315I gatekeeper mutation that confers
    resistance to other TKIs. Reserved for patients with T315I mutation or failure
    of multiple prior TKIs due to cardiovascular risks.
  pdb_structures:
  - pdb_id: 3OXZ
    description: Ponatinib bound to native ABL1 kinase domain, showing how the linear ethynyl linker avoids the T315I steric clash that blocks imatinib binding at the gatekeeper residue
    resolution_angstrom: 1.8
    method: X-ray
    ligand: ponatinib
    target_protein: ABL1 kinase domain
    publication: PMID:21060979
  - pdb_id: 1IEP
    description: Imatinib/ABL1 co-crystal — T315 forms a hydrogen bond with imatinib that is lost upon T315I mutation, explaining gatekeeper resistance
    resolution_angstrom: 2.1
    method: X-ray
    ligand: imatinib
    target_protein: ABL1 kinase domain (wild-type reference for resistance mapping)
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: ponatinib
      term:
        id: CHEBI:78543
        label: ponatinib
  evidence:
  - reference: PMID:11423618
    reference_title: "Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification."
    supports: SUPPORT
    snippet: "In six of nine patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution of threonine with isoleucine was sufficient to confer STI-571 resistance."
    explanation: This paper identified the T315I gatekeeper mutation that confers resistance to first and second-generation TKIs, establishing the need for third-generation TKIs like ponatinib.
  - reference: CIVIC_EID:234
    reference_title: "BCR::ABL1 Fusion AND ABL1 T315I / Chronic Myeloid Leukemia (Predictive Resistance)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In chronic myeloid leukemia patients with the ABL T315I mutation, tumors have shown to be resistant to imatinib treatment.
    explanation: CIViC's accepted evidence item supports T315I as an imatinib-resistance marker, which is the rationale for T315I-active later-generation TKIs such as ponatinib.
- name: Allogeneic Stem Cell Transplantation
  description: >-
    Potentially curative option historically used as primary therapy before TKI era.
    Now reserved for patients failing multiple TKIs, those with T315I mutation
    without ponatinib access, or blast crisis. Significant morbidity and mortality risks.
  treatment_term:
    preferred_term: Allogeneic Stem Cell Transplantation
    term:
      id: NCIT:C201466
      label: Allogeneic Stem Cell Transplantation
  evidence:
  - reference: PMID:10428738
    reference_title: "Chronic myelogenous leukemia: biology and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      allogeneic stem-cell transplantation has provided the groundwork for a
      cure of chronic myelogenous leukemia
    explanation: >-
      This review documents allogeneic stem-cell transplantation as the
      established potentially curative therapy for CML.

discussions:
- discussion_id: cml_cdh2_gsk3beta_translational_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Uncontrolled Myeloid Proliferation
  - pathophysiology#Constitutive Tyrosine Kinase Activation
  - pathophysiology#PI3K-AKT Pathway Activation
  - pathophysiology#JAK-STAT Pathway Activation
  prompt: >-
    Does CDH2 (N-cadherin) mediated GSK3β-sensitive suppression of proliferation
    observed in K562 leukemia cells represent a tractable therapeutic vulnerability
    in human CML, or is it a cell-line artifact without relevance to BCR-ABL1 driven
    pathophysiology?
  rationale: >-
    K562 CML cells represent a well-established model but may diverge from primary
    CML stem cells and patient-derived xenografts in GSK3β signaling and CDH2 expression
    context. CDH2 exhibits pan-cancer context-dependent effects, suggesting that
    anti-proliferative phenotype in K562 cells may not generalize to human CML. The
    paper's own conclusion notes "the precise molecular mechanism remains unresolved"
    and identifies this as a "therapeutic vulnerability in this model" — language
    that appropriately caveat-gates claims to the K562 cell line. Clarifying whether
    the CDH2-GSK3β axis operates as a disease mechanism (not just in vitro drug target)
    is mechanistically meaningful for CML's relationship to Wnt/β-catenin and MAPK
    checkpoint signaling.
  proposed_experiments:
  - experiment_id: exp_cml_cdh2_gsk3beta_primary_cells
    name: CDH2-GSK3β axis validation in primary CML progenitors and patient-derived xenografts
    description: >-
      Quantify CDH2 and GSK3β expression levels in primary CML stem cells (CD34+),
      patient-derived xenografts (PDX), and K562 cells to determine whether K562
      model recapitulates the expression and signaling context of human disease.
      Test whether CDH2 overexpression or GSK3β inhibition (CHIR-99,021) suppresses
      proliferation in primary human CML progenitors or PDX models matching K562
      phenotype. If the effect does not replicate, the mechanism is K562-specific.
    experiment_type:
      preferred_term: gene-perturbation proliferation assay in primary progenitors and xenografts
    model_systems:
    - name: Primary CML CD34+ progenitor culture
      description: >-
        Patient-derived CD34+ chronic myeloid leukemia stem/progenitor cells,
        the primary-cell context against which the K562 CDH2-GSK3β phenotype is
        tested for translational validity.
      experimental_model_type: PRIMARY_CELL_CULTURE
    - name: CML patient-derived xenograft (PDX)
      description: >-
        In vivo engraftment of primary CML cells used to assess whether CDH2
        overexpression or GSK3β inhibition reproduces the K562 anti-proliferative
        effect in a disease-faithful microenvironment.
      experimental_model_type: OTHER
    - name: K562 CML cell line
      description: >-
        The immortalized BCR-ABL1-positive cell line in which the original
        CDH2-GSK3β-sensitive anti-proliferative effect was observed.
      experimental_model_type: CELL_LINE
  - experiment_id: exp_cml_cdh2_bcr_abl1_intersection
    name: Mechanistic intersection of CDH2-GSK3β axis with BCR-ABL1 signaling
    description: >-
      Map CDH2-GSK3β axis to BCR-ABL1 signaling: determine whether CDH2 upregulation
      suppresses BCR-ABL1-driven proliferation through MAPK/PI3K/JAK-STAT checkpoint
      effects, or through an off-axis Wnt/GSK3β-independent route. Mechanistically
      contextualize CDH2 effects within the documented CML pathophysiology nodes
      (Uncontrolled Myeloid Proliferation, Constitutive Tyrosine Kinase Activation,
      PI3K-AKT Pathway Activation, JAK-STAT Pathway Activation).
    experiment_type:
      preferred_term: signaling-pathway epistasis mapping assay
    model_systems:
    - name: K562 CML cell line
      description: >-
        BCR-ABL1-positive cell line used to map the CDH2-GSK3β axis onto
        BCR-ABL1 downstream checkpoint signaling (MAPK/PI3K/JAK-STAT).
      experimental_model_type: CELL_LINE
    - name: Primary CML CD34+ progenitor culture
      description: >-
        Patient-derived CD34+ progenitors used to confirm any BCR-ABL1
        intersection observed in the K562 model in disease-relevant cells.
      experimental_model_type: PRIMARY_CELL_CULTURE
  evidence:
  - reference: PMID:42401590
    reference_title: "Pan-cancer profiling of CDH2 and a GSK3β-sensitive anti-proliferative effect in K562 chronic myeloid leukemia cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CDH2 overexpression suppressed proliferation, induced cell cycle arrest and
      early apoptosis. This was accompanied by increased total β-catenin protein
      but a reduced nuclear-to-cytoplasmic β-catenin ratio, without consistent
      changes in canonical Wnt target gene expression. Notably, the GSK3 inhibitor
      CHIR-99,021 reversed the anti-proliferative effect of CDH2, whereas the
      β-catenin degrader MSAB did not rescue it. CDH2 exhibits context-dependent
      expression across malignancies. In K562 CML cells, CDH2 overexpression
      suppresses proliferation through a GSK3β-sensitive mechanism. However, the
      precise molecular mechanism remains unresolved.
    explanation: >-
      This IN_VITRO evidence from K562 cells demonstrates CDH2-GSK3β-sensitive
      anti-proliferation but explicitly acknowledges mechanistic uncertainty and
      context-dependence across cancer types, indicating that human validation is
      required to interpret this as a generalizable CML mechanism rather than a
      K562 cell-line artifact.

disease_term:
  preferred_term: chronic myeloid leukemia
  term:
    id: MONDO:0011996
    label: chronic myelogenous leukemia, BCR-ABL1 positive

gene_sets:
- gene_set: MYGENESET:KEGG_CHRONIC_MYELOID_LEUKEMIA
  relationship: CANONICAL_PATHWAY
  note: >-
    KEGG chronic myeloid leukemia pathway (BCR-ABL).
classifications:
  icdo_morphology:
    classification_value: Leukemia
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
📚

References & Deep Research

Deep Research

2
Disorder ▸

Disorder

  • Name: Chronic Myeloid Leukemia, BCR-ABL1 Positive
  • Category:
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 19

Key Pathophysiology Nodes

  • BCR-ABL1 Fusion Oncogene Formation
  • Constitutive Tyrosine Kinase Activation
  • RAS-MAPK Pathway Hyperactivation
  • PI3K-AKT Pathway Activation
  • JAK-STAT Pathway Activation
  • Reactive Oxygen Species Generation
  • Uncontrolled Myeloid Proliferation
  • Apoptosis Resistance
  • Genomic Instability and Disease Progression
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s11899-023-00688-6
  • DOI:10.1007/s12672-024-01444-9
  • DOI:10.1038/s41375-025-02664-w
  • DOI:10.1038/s41467-023-40222-z
  • DOI:10.1111/ejh.70006
  • DOI:10.1182/blood.2022016896
  • DOI:10.2147/jbm.s382090
  • DOI:10.31640/ls-2025-4-29
  • DOI:10.3389/fonc.2025.1546813
  • DOI:10.3389/fphar.2025.1615770
  • DOI:10.3390/hematolrep17020018
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 42 citations 2026-01-24T18:55:06.842924

Disease Pathophysiology Research Report

Target Disease - Disease Name: Chronic Myeloid Leukemia, BCR-ABL1 Positive - MONDO ID: not unambiguously specified in the retrieved sources - Category: Myeloproliferative neoplasm (leukemia)

Pathophysiology description (current understanding) Chronic myeloid leukemia (CML) is initiated by the BCR::ABL1 fusion oncoprotein, a constitutively active tyrosine kinase that induces aberrant signaling, altered adhesion, enhanced survival, and self-renewal of leukemic progenitors and stem cells. Persistent leukemic stem cells (LSCs) survive despite tyrosine kinase inhibitors (TKIs) through bone marrow niche protection and BCR-ABL1–independent programs, including metabolic adaptations. Niche-derived cues such as the CXCL12–CXCR4 axis, LSC-expressed CD26 (DPP4), and altered stromal cytokines (e.g., reduced CXCL14) modulate homing, quiescence, and therapy resistance. Immune evasion involves PD-1/PD-L1 pathways and immune-modulatory extracellular vesicles; immune cell phenotypes, notably mature NK cells, correlate with treatment-free remission (TFR). Clonal evolution with additional mutations (ASXL1, RUNX1, IKZF1, TP53) and additional cytogenetic abnormalities underpins progression to accelerated/blast phase. (sicuranza2025thebiologyof pages 1-2, patterson2023thebonemarrow pages 1-2, dolinska2023characterizationofthe pages 14-26, rinaldi2023chronicmyeloidleukemia pages 2-4, pratiwi2025geneticprofilingof pages 23-24)

1) Core Pathophysiology: primary mechanisms, dysregulated pathways, affected cellular processes - BCR-ABL1 downstream signaling - STAT5: Constitutive activation of STAT5 promotes anti-apoptotic transcription (e.g., BCL-xL) and proliferation in BCR-ABL1+ cells. “The 210 kDa BCR::ABL1 oncoprotein has constitutively active tyrosine kinase activity that stimulates multiple downstream signaling pathways,” including STAT signaling. (Frontiers in Oncology review, 2025; DOI: https://doi.org/10.3389/fonc.2025.1546813) (sicuranza2025thebiologyof pages 1-2) - RAS/MAPK: BCR-ABL1 engages Ras→Raf–MEK–ERK cascades that drive proliferation and survival. (Frontiers in Pharmacology review, 2025; DOI: https://doi.org/10.3389/fphar.2025.1615770) (alqahtani2025potentialsignalingpathways pages 5-6) - PI3K/AKT: BCR-ABL1 activates PI3K/AKT to suppress apoptosis (e.g., BAD inactivation) and support growth; crosstalk with ERK can modulate pathway balance. (Frontiers in Pharmacology, 2025) (alqahtani2025potentialsignalingpathways pages 5-6) - Cellular processes dysregulated - Survival/anti-apoptosis, proliferation, adhesion changes, and self-renewal acquisition are central effects of BCR-ABL1 signaling on hematopoietic progenitors and LSCs. (Frontiers in Oncology, 2025; URL above) (sicuranza2025thebiologyof pages 1-2) - Bone-marrow microenvironment (BME) protection drives LSC quiescence and TKI resistance, involving chemokine axes and adhesion molecules. (Curr Hematol Malig Rep, 2023; DOI: https://doi.org/10.1007/s11899-023-00688-6) (patterson2023thebonemarrow pages 1-2)

2) Key Molecular Players - Genes/Proteins (HGNC) - BCR (HGNC:1014)–ABL1 (HGNC:76): driver fusion. (sicuranza2025thebiologyof pages 1-2) - STAT5A/STAT5B (HGNC:11366/11367), NRAS (HGNC:7989), KRAS (HGNC:6407), PIK3CA (HGNC:8975), AKT1 (HGNC:391): principal downstream nodes. (alqahtani2025potentialsignalingpathways pages 5-6) - CXCL12 (HGNC:10672), CXCR4 (HGNC:2561), DPP4/CD26 (HGNC:3009), CD44 (HGNC:1681), IL1RAP (HGNC:5994), CD36 (HGNC:1663): niche/adhesion/metabolic entry points. (patterson2023thebonemarrow pages 1-2) - CXCL14 (HGNC:10648): niche cytokine; downregulated in CML stromal cells. (dolinska2023characterizationofthe pages 14-26) - MPC1 (HGNC:27464), PC (pyruvate carboxylase; HGNC:8638), MYC (HGNC:7553), MTOR (HGNC:3942): metabolic and signaling regulators in LSCs. (dolinska2023characterizationofthe pages 14-26, rinaldi2023chronicmyeloidleukemia pages 2-4) - PDCD1/PD-1 (HGNC:8764), CD274/PD-L1 (HGNC:16958), FOXP3 (HGNC:6106): immune checkpoints and regulatory programs. (patterson2023thebonemarrow pages 1-2, sicuranza2025thebiologyof pages 1-2) - ASXL1 (HGNC:18074), RUNX1 (HGNC:10471), IKZF1 (HGNC:13176), TP53 (HGNC:11998): lesions associated with progression. (pratiwi2025geneticprofilingof pages 23-24) - Chemical entities (CHEBI) - TKIs: imatinib (CHEBI:45783), dasatinib (CHEBI:49375), nilotinib (CHEBI:52174), bosutinib (CHEBI:53165), ponatinib (CHEBI:65115); STAMP inhibitor asciminib (CHEBI not specified in sources). (sicuranza2025thebiologyof pages 1-2) - Metabolites: glutamine (CHEBI:18050), fatty acid (CHEBI:35366) linked to FA uptake/oxidation in LSCs. (patterson2023thebonemarrow pages 1-2, dolinska2023characterizationofthe pages 14-26) - Cell types (CL) - Hematopoietic stem cell (CL:0000037)/LSC; NK cell (CL:0000623); T cell (CL:0000084); myeloid progenitors. (patterson2023thebonemarrow pages 1-2, dolinska2023characterizationofthe pages 14-26) - Anatomical locations (UBERON) - Bone marrow (UBERON:0002371) and splenic microenvironments (UBERON:0002106) for niche interactions and extramedullary hematopoiesis. (patterson2023thebonemarrow pages 1-2)

3) Biological Processes for GO annotation (disrupted processes) - Signal transduction (GO:0007165); transmembrane receptor protein tyrosine kinase signaling pathway (GO:0007169); MAPK cascade (GO:0000165); PI3K signaling (GO:0014065); JAK-STAT cascade (GO:0007259). BCR-ABL1 constitutively activates these pathways to promote survival and proliferation. (sicuranza2025thebiologyof pages 1-2, alqahtani2025potentialsignalingpathways pages 5-6) - Negative regulation of apoptotic process (GO:0043066) via STAT5/PI3K-AKT effectors; positive regulation of cell proliferation (GO:0008284). (alqahtani2025potentialsignalingpathways pages 5-6) - Chemokine-mediated signaling pathway (GO:0070098): CXCL12–CXCR4 controls homing/quiescence and TKI resistance. (patterson2023thebonemarrow pages 1-2) - mTOR signaling (GO:0031929): CXCL14 suppresses mTORC1 targets in CML LSCs. (dolinska2023characterizationofthe pages 14-26) - Oxidative phosphorylation (GO:0006119) and fatty-acid beta-oxidation (GO:0006635): enhanced reliance in LSCs; pyruvate transport (GO:0006843) and anaplerosis sustain TCA/OXPHOS under TKI pressure. (rinaldi2023chronicmyeloidleukemia pages 2-4)

4) Cellular Components - Plasma membrane (GO:0005886) for receptors (CXCR4, IL1RAP, CD26, CD44, CD36, PD-1/PD-L1). (patterson2023thebonemarrow pages 1-2) - Mitochondrion (GO:0005739) for OXPHOS, fatty-acid oxidation, and pyruvate transport (MPC1/2). (rinaldi2023chronicmyeloidleukemia pages 2-4) - Cytosol/nucleus (GO:0005829/GO:0005634) for signal transducers (STAT5, AKT) and transcriptional programs (MYC). (sicuranza2025thebiologyof pages 1-2, alqahtani2025potentialsignalingpathways pages 5-6) - Bone marrow extracellular space/microenvironment (GO:0005615 context; UBERON:0002371 anatomical) for chemokines (CXCL12, CXCL14) and stromal interactions. (dolinska2023characterizationofthe pages 14-26, patterson2023thebonemarrow pages 1-2)

5) Disease Progression: sequence of events and phases - Initiation: Acquisition of BCR::ABL1 in a hematopoietic stem/progenitor cell creates a constitutive kinase driving clonal expansion and displacement of normal hematopoiesis. (sicuranza2025thebiologyof pages 1-2) - Chronic phase: Proliferation of mature myeloid cells with leukocytosis and splenomegaly; persistent LSCs are protected by niche signals (CXCL12–CXCR4, adhesion) and metabolic adaptations. (patterson2023thebonemarrow pages 1-2) - Progression: Genomic instability and clonal evolution with additional cytogenetic abnormalities (e.g., +8, +19, i(17q), double Ph) and mutations (ASXL1, RUNX1, IKZF1, TP53) lead to accelerated and blast phases. (rinaldi2023chronicmyeloidleukemia pages 2-4, pratiwi2025geneticprofilingof pages 23-24) - Notable microenvironmental shift: “CXCL14 is lost in BM stromal cells in patients with CML, and restoring CXCL14 suppresses CML LSC engraftment in vivo and survival in vitro,” supporting niche-driven control of LSC metabolism (mTOR/OXPHOS) and potential progression restraint. (Blood, 2023; DOI: https://doi.org/10.1182/blood.2022016896) (dolinska2023characterizationofthe pages 14-26)

6) Phenotypic Manifestations (HP terms) and mechanistic links - Leukocytosis (HP:0001974), thrombocytosis (HP:0001873), anemia (HP:0001903), splenomegaly (HP:0001744), fatigue (HP:0012378), night sweats (HP:0031068) relate to cytokine-driven myeloproliferation and extramedullary hematopoiesis in chronic phase. (rinaldi2023chronicmyeloidleukemia pages 2-4) - Blast crisis: cytopenias, marrow failure due to accumulation of blasts, often with RUNX1/TP53 mutations and additional cytogenetic lesions. (pratiwi2025geneticprofilingof pages 23-24)

Recent developments and latest research (prioritized 2023–2025) - Bone marrow niche and CXCL14: Blood (2023) demonstrated niche remodeling with reduced CXCL14 expression in CML MSCs; exogenous CXCL14 acutely suppresses mTORC1, OXPHOS and MYC target gene sets in LSC-enriched CD34+CD38− cells and reduces LSC survival and engraftment. (“CXCL14 is lost in BM stromal cells… CXCL14 treatment inhibits mTOR and oxidative phosphorylation signaling pathways in CML LSCs.”) (https://doi.org/10.1182/blood.2022016896; Apr 2023) (dolinska2023characterizationofthe pages 14-26) - LSC metabolism and pyruvate anaplerosis: Nature Communications (2023) identified persistent pyruvate anaplerosis as a vulnerability in TKI-treated CML LSCs; genetic or pharmacologic inhibition of the mitochondrial pyruvate carrier (MPC1/2; MSDC‑0160) sensitized LSCs to imatinib in patient-derived models. (https://doi.org/10.1038/s41467-023-40222-z; Aug 2023) (rinaldi2023chronicmyeloidleukemia pages 2-4) - Immune microenvironment and NK/T cell phenotypes: Current Hematologic Malignancy Reports (2023) reviewed evidence that NK phenotypes correlate with sustained TFR, and detailed how CXCL12–CXCR4, CD26, CD44, and exosomal cross-talk enforce quiescence and TKI resistance, informing BME-targeted combinatorial strategies. (https://doi.org/10.1007/s11899-023-00688-6; Feb 2023) (patterson2023thebonemarrow pages 1-2, patterson2023thebonemarrow pages 2-5, patterson2023thebonemarrow pages 5-6) - Progression genetics: Contemporary reviews (2023–2025) emphasize ASXL1 as a recurrent adverse lesion, with RUNX1, IKZF1, and TP53 commonly implicated in blast-phase transformation; TP53 is uncommon in chronic phase but present in up to ~30% of blast crisis and portends poor outcomes. (https://doi.org/10.2147/jbm.s382090; Apr 2023. https://doi.org/10.3390/hematolrep17020018; Mar 2025) (rinaldi2023chronicmyeloidleukemia pages 2-4, pratiwi2025geneticprofilingof pages 24-25, pratiwi2025geneticprofilingof pages 23-24) - ELN 2025 guidance: Leukemia (2025) updates highlight individualized TKI selection, dose adjustments, discontinuation data maturity, and the importance of immune-mediated control of residual disease; WHO reclassification of CML as biphasic is noted. (https://doi.org/10.1038/s41375-025-02664-w; Jul 2025) (rinaldi2023chronicmyeloidleukemia pages 13-14)

Current applications and real-world implementations (MRD/TFR and monitoring) - MRD definitions and technologies - Molecular response thresholds: MR4 (≤0.01% IS), MR4.5 (≤0.0032% IS), MR5 (≤0.001% IS) by standardized qPCR (International Scale). (Hematology Reports, 2025; https://doi.org/10.3390/hematolrep17020018) (pratiwi2025geneticprofilingof pages 24-25) - Digital PCR (dPCR): Increasingly used for ultra-low–level detection; dPCR often detects DMR earlier than qPCR and more accurately identifies stable DMR, which is relevant to TFR selection. (Likarska sprava, 2025; https://doi.org/10.31640/ls-2025-4-29) (гордіичук2025precisionmonitoringin pages 3-5) - TFR rates and predictors - Meta-analysis of 19 single-arm trials (n=2336): Overall mean TFR 59% at 12 months and 55% at 24 months; deeper response (MR5.0) and prior interferon exposure associate with higher TFR; no CML-related deaths reported in TFR cohorts. (Discover Oncology, 2024; https://doi.org/10.1007/s12672-024-01444-9) (zheng2024treatmentfreeremissionafter pages 1-3, zheng2024treatmentfreeremissionafter pages 8-12) - Real-world cohort (n=118): Estimated molecular-relapse–free survival 79.7% at 6 months and 69.9% overall (loss of MMR defined relapse); shorter stable DMR (<5 years), unstable prior DMR, and high Sokal risk predicted shorter TFR (BASE‑TFR score). (Eur J Haematol, 2025; https://doi.org/10.1111/ejh.70006) (lagana2025treatmentfreeremission pages 1-2) - Immune correlates: Mature NK cell enrichment associates with maintained TFR in multiple analyses; loss of major molecular response (MMR) is commonly used to define relapse thresholds. (J Blood Med, 2023; Discover Oncology, 2024) (rinaldi2023chronicmyeloidleukemia pages 8-9, zheng2024treatmentfreeremissionafter pages 12-13) - Monitoring intervals (consensus/guidelines) - While specific schedules vary by guideline, ELN/NCCN-based recommendations emphasize intensive monitoring in the first year of TFR (e.g., monthly to every 6 weeks initially, then spacing to quarterly and semi-annually), with lifelong molecular surveillance due to most relapses occurring within 6–12 months. (Discover Oncology, 2024; Leukemia, 2025) (zheng2024treatmentfreeremissionafter pages 12-13, rinaldi2023chronicmyeloidleukemia pages 13-14)

Expert opinions and authoritative synthesis - Patterson & Copland (2023) argue that overcoming the protective bone-marrow immune microenvironment is essential to eradicate TKI-persistent LSCs, highlighting CXCL12–CXCR4, CD26, CD44, and exosomal crosstalk as therapeutic vulnerabilities and linking NK phenotypes to durable TFR. (https://doi.org/10.1007/s11899-023-00688-6) (patterson2023thebonemarrow pages 1-2) - Dolinska et al. (Blood, 2023) identify CXCL14 loss in the CML marrow niche and demonstrate that restoring CXCL14 suppresses LSC metabolism and survival, positioning CXCL14 as a candidate adjunct to target LSC persistence. (https://doi.org/10.1182/blood.2022016896) (dolinska2023characterizationofthe pages 14-26) - Rattigan et al. (Nat Commun, 2023) propose mitochondrial pyruvate transport/anaplerosis as a persistent vulnerability in CML LSCs, even under TKI, enabling rational metabolic combinations. (https://doi.org/10.1038/s41467-023-40222-z) (rinaldi2023chronicmyeloidleukemia pages 2-4) - ELN 2025 (Leukemia) emphasizes individualized TKI management, growing evidence for discontinuation strategies, and the reality that many patients will require long-term therapy—keeping quality of life and side-effect minimization central. (https://doi.org/10.1038/s41375-025-02664-w) (rinaldi2023chronicmyeloidleukemia pages 13-14)

Relevant statistics and data - Pooled TFR rates after TKI stop: 59% at 12 months; 55% at 24 months (19 studies; 2336 patients). Better TFR with MR5.0 (62% at 24 months) and prior IFN exposure. No CML-related deaths during TFR across included studies. (https://doi.org/10.1007/s12672-024-01444-9; Oct 2024) (zheng2024treatmentfreeremissionafter pages 1-3, zheng2024treatmentfreeremissionafter pages 8-12) - Real-world TFR maintenance ~70% overall with relapse defined as loss of MMR; risk factors include high Sokal, DMR <5 years, prior unstable DMR (BASE‑TFR score). (https://doi.org/10.1111/ejh.70006; Jun 2025) (lagana2025treatmentfreeremission pages 1-2) - Progression lesions: TP53 alterations uncommon in chronic phase but seen in up to ~30% of blast crisis and associate with poor prognosis; ASXL1 frequently linked to adverse outcomes and transformation risk. (https://doi.org/10.3390/hematolrep17020018; Mar 2025) (pratiwi2025geneticprofilingof pages 24-25, pratiwi2025geneticprofilingof pages 23-24)

Evidence artifact | Category | Key item(s) (HGNC / ontology where applicable) | Mechanistic / clinical note | Evidence (year, DOI/URL) | Context IDs | |---|---|---|---|---| | BCR-ABL1 downstream signaling | STAT5 (STAT5A/B), RAS/MAPK (NRAS/KRAS), PI3K/AKT (PIK3CA/AKT1) | Constitutive BCR-ABL1 tyrosine kinase activity drives STAT5, RAS–MAPK and PI3K–AKT activation → increased proliferation, survival (anti‑apoptotic transcription like BCL‑xL) and altered adhesion. | 2025, Sicuranza A et al., Front. Oncol., DOI:10.3389/fonc.2025.1546813; 2025, Alqahtani S., Front. Pharmacol., DOI:10.3389/fphar.2025.1615770 | (sicuranza2025thebiologyof pages 1-2, alqahtani2025potentialsignalingpathways pages 5-6) | | LSC niche factors | CXCL12 / CXCR4 (CXCL12, CXCR4), CD26 (DPP4), CD44, IL1RAP, CD36 | Niche chemokine CXCL12–CXCR4 axis maintains LSC quiescence and TKI resistance; CD26 on LSCs cleaves CXCL12 (disrupts homing) and correlates with disease burden; CD44, IL1RAP and CD36 mediate adhesion, immune interactions and fatty‑acid uptake supporting LSC survival. | 2023, Patterson & Copland, Curr. Hematol. Malig. Rep., DOI:10.1007/s11899-023-00688-6; 2023, Dolinska M. et al., Blood, DOI:10.1182/blood.2022016896 | (patterson2023thebonemarrow pages 1-2, dolinska2023characterizationofthe pages 14-26) | | Niche cytokine CXCL14 | CXCL14 (CXCL14) | CXCL14 is downregulated in CML bone‑marrow MSCs; exogenous CXCL14 suppresses mTORC1 signalling, OXPHOS and MYC target gene sets in CD34+CD38− (LSC‑enriched) cells → reduced mitochondrial activity and LSC survival. | 2023, Dolinska M. et al., Blood, DOI:10.1182/blood.2022016896 | (dolinska2023characterizationofthe pages 14-26) | | LSC metabolism — OXPHOS / pyruvate anaplerosis & MPC | MPC1/2 (MPC1), Pyruvate carboxylase (PC), CD36 | CML LSCs show reliance on mitochondrial metabolism (OXPHOS, FAO) and enhanced pyruvate anaplerosis; inhibition of mitochondrial pyruvate carrier (MPC1/2) (e.g., MSDC‑0160) or targeting FA uptake sensitizes persistent LSCs to TKIs in preclinical models. | 2023, Rattigan KM et al., Nat Commun., DOI:10.1038/s41467-023-40222-z; 2023, Dolinska M. et al., Blood, DOI:10.1182/blood.2022016896; 2025, Sicuranza A. et al., Front. Oncol., DOI:10.3389/fonc.2025.1546813 | (dolinska2023characterizationofthe pages 14-26, sicuranza2025thebiologyof pages 1-2, rinaldi2023chronicmyeloidleukemia pages 2-4) | | Immune evasion (PD‑1/PD‑L1, NK phenotypes) | PDCD1 (PD‑1), CD274 (PD‑L1), NK markers (NCAM1/CD56, FCGR3A/CD16, CD57) | CML‑derived EVs and niche signals upregulate immunoregulatory programs (including PD‑1/PD‑L1, FOXP3/IL‑10), promoting T‑cell dysfunction; higher proportions of mature NK cells (CD57+CD16+) associate with durable TFR in cohorts. | 2023, Patterson & Copland, Curr. Hematol. Malig. Rep., DOI:10.1007/s11899-023-00688-6; 2025, Sicuranza A. et al., Front. Oncol., DOI:10.3389/fonc.2025.1546813; 2024, Zheng Z. et al., Discover Oncol., DOI:10.1007/s12672-024-01444-9 | (patterson2023thebonemarrow pages 1-2, sicuranza2025thebiologyof pages 1-2, zheng2024treatmentfreeremissionafter pages 1-3) | | Progression lesions and ACAs | ASXL1, RUNX1, IKZF1, TP53; common ACAs (+8, +19, i(17q), double Ph) | Somatic mutations in epigenetic regulators (ASXL1), transcription factors (RUNX1, IKZF1) and TP53, plus acquisition of additional cytogenetic abnormalities, correlate with TKI resistance, clonal evolution and transformation to accelerated/blast phase. | 2023, Rinaldi I. & Winston K., J. Blood Med., DOI:10.2147/jbm.s382090; 2025, Pratiwi L. et al., Hematol. Rep., DOI:10.3390/hematolrep17020018; 2025, Sicuranza A. et al., Front. Oncol., DOI:10.3389/fonc.2025.1546813 | (rinaldi2023chronicmyeloidleukemia pages 2-4, pratiwi2025geneticprofilingof pages 23-24, sicuranza2025thebiologyof pages 1-2) | | MRD / TFR — definitions, rates, predictors & monitoring | MR4 (≤0.01% IS), MR4.5 (≤0.0032% IS), MR5 (≤0.001% IS); assays: qPCR (IS), dPCR, NGS | Meta‑analysis pooled TFR: ~59% at 12 months and ~55% at 24 months after TKI stop; stronger predictors = deeper MR (MR5), longer DMR duration, prior interferon exposure, selected immunologic features (NK/CTL); qPCR (IS) is standard; dPCR offers greater sensitivity and earlier DMR detection. | 2024, Zheng Z. et al., Discover Oncol., DOI:10.1007/s12672-024-01444-9; 2025, Laganà A. et al., Eur. J. Haematol., DOI:10.1111/ejh.70006; 2025 (lab recs), dPCR studies DOI cited in pqac-00000018 | (zheng2024treatmentfreeremissionafter pages 1-3, lagana2025treatmentfreeremission pages 1-2, гордіичук2025precisionmonitoringin pages 3-5) | | ELN guidance & BCR‑ABL1‑independent LSC persistence | ELN 2025 recommendations; BME (MSCs, cytokines) | Recent ELN guidance updates management and recognizes BCR‑ABL1‑independent mechanisms of persistence; LSCs are sustained by bone‑marrow niche interactions making eradication challenging — rationale for niche‑directed adjuncts to TKIs. | 2025, Apperley JF. et al., Leukemia, DOI:10.1038/s41375-025-02664-w; 2023, Patterson & Copland, Curr. Hematol. Malig. Rep., DOI:10.1007/s11899-023-00688-6 | (rinaldi2023chronicmyeloidleukemia pages 13-14, patterson2023thebonemarrow pages 1-2) |

Table: Concise evidence table summarizing key molecular, niche, metabolic, immune, genetic and clinical (MRD/TFR) items in BCR‑ABL1+ CML with 2023–2025 sources and supporting context IDs; useful for populating a disease knowledge base or rapid reference.

Gene/protein annotations with ontology terms (selected examples) - BCR::ABL1 (fusion): HGNC:1014 (BCR), HGNC:76 (ABL1); Processes: GO:0007169, GO:0007165; Components: GO:0005886, GO:0005634. (sicuranza2025thebiologyof pages 1-2) - STAT5A/B (HGNC:11366/11367); Process: GO:0007259; Function in CML: pro-survival transcription downstream of BCR-ABL1. (alqahtani2025potentialsignalingpathways pages 5-6) - NRAS/KRAS (HGNC:7989/6407); Process: GO:0000165; role: proliferation, survival. (alqahtani2025potentialsignalingpathways pages 5-6) - PIK3CA/AKT1 (HGNC:8975/391); Process: GO:0014065; role: anti-apoptosis, growth. (alqahtani2025potentialsignalingpathways pages 5-6) - CXCL12 (HGNC:10672)/CXCR4 (HGNC:2561); Process: GO:0070098; Component: GO:0005886; role: LSC homing/quiescence and TKI resistance. (patterson2023thebonemarrow pages 1-2) - DPP4/CD26 (HGNC:3009); Process: chemokine processing; role: cleaves CXCL12 to disrupt homing. (patterson2023thebonemarrow pages 1-2) - CXCL14 (HGNC:10648); Process: GO:0031929 (mTOR signaling regulation); role: suppresses mTOR/OXPHOS programs in LSCs. (dolinska2023characterizationofthe pages 14-26) - MPC1 (HGNC:27464)/PC (HGNC:8638); Process: GO:0006843 (pyruvate transport), GO:0006099 (TCA); role: pyruvate anaplerosis supporting LSC OXPHOS; therapeutic target via MPC inhibition. (rinaldi2023chronicmyeloidleukemia pages 2-4) - PDCD1 (HGNC:8764)/CD274 (HGNC:16958); Process: immune checkpoint signaling; role: T-cell exhaustion/immune evasion in CML milieu. (patterson2023thebonemarrow pages 1-2, sicuranza2025thebiologyof pages 1-2) - ASXL1 (HGNC:18074), RUNX1 (HGNC:10471), IKZF1 (HGNC:13176), TP53 (HGNC:11998); Processes: chromatin regulation, hematopoietic transcription, DNA damage response; role: progression to AP/BP, poor outcomes. (pratiwi2025geneticprofilingof pages 23-24)

Phenotype associations (HP terms) - HP:0001974 Leukocytosis; HP:0001873 Thrombocytosis; HP:0001903 Anemia; HP:0001744 Splenomegaly; HP:0012378 Fatigue; HP:0031068 Night sweats. Mechanistic links: BCR-ABL1–driven myeloproliferation; extramedullary hematopoiesis; cytokine milieu. (rinaldi2023chronicmyeloidleukemia pages 2-4)

Cell type involvement (CL terms) - CL:0000037 Hematopoietic stem cell/LSC; CL:0000623 NK cell; CL:0000084 T cell; CL:0000842 Myeloid progenitor cell. (patterson2023thebonemarrow pages 1-2, dolinska2023characterizationofthe pages 14-26)

Anatomical locations (UBERON terms) - UBERON:0002371 Bone marrow; UBERON:0002106 Spleen. (patterson2023thebonemarrow pages 1-2)

Chemical entities (CHEBI) - CHEBI:45783 imatinib; CHEBI:49375 dasatinib; CHEBI:52174 nilotinib; CHEBI:53165 bosutinib; CHEBI:65115 ponatinib. (sicuranza2025thebiologyof pages 1-2) - CHEBI:18050 L-glutamine; CHEBI:35366 fatty acid (LSC metabolic context). (patterson2023thebonemarrow pages 1-2, dolinska2023characterizationofthe pages 14-26)

Evidence items with URLs and dates (selection) - Dolinska M. et al., Blood, 2023-04: “CXCL14 is lost in BM stromal cells in patients with CML… CXCL14 treatment inhibits mTOR and oxidative phosphorylation signaling pathways in CML LSCs.” URL: https://doi.org/10.1182/blood.2022016896 (dolinska2023characterizationofthe pages 14-26) - Rattigan KM. et al., Nat Commun., 2023-08: “Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells.” URL: https://doi.org/10.1038/s41467-023-40222-z (rinaldi2023chronicmyeloidleukemia pages 2-4) - Patterson & Copland, Curr Hematol Malig Rep., 2023-02: bone marrow immune microenvironment in CML and TFR correlates. URL: https://doi.org/10.1007/s11899-023-00688-6 (patterson2023thebonemarrow pages 1-2) - Zheng Z. et al., Discover Oncology, 2024-10: meta-analysis of TFR after TKI discontinuation with 12- and 24-month rates and predictors. URL: https://doi.org/10.1007/s12672-024-01444-9 (zheng2024treatmentfreeremissionafter pages 1-3, zheng2024treatmentfreeremissionafter pages 8-12) - Laganà A. et al., Eur J Haematol., 2025-06: real-world TFR outcomes and BASE‑TFR score. URL: https://doi.org/10.1111/ejh.70006 (lagana2025treatmentfreeremission pages 1-2) - Apperley JF. et al., Leukemia (ELN 2025), 2025-07: updated ELN recommendations. URL: https://doi.org/10.1038/s41375-025-02664-w (rinaldi2023chronicmyeloidleukemia pages 13-14)

Direct quotes (where available) - “CXCL14 is lost in BM stromal cells in patients with CML, and restoring CXCL14 suppresses CML LSC engraftment in vivo and survival in vitro. CXCL14 treatment inhibits mTOR and oxidative phosphorylation signaling pathways in CML LSCs.” (Blood, 2023) (dolinska2023characterizationofthe pages 14-26) - Meta-analysis summary: 19 trials, “overall mean TFR rate of 59% at 12 months and 55% at 24 months,” with “prior interferon therapy and attainment of MR5.0… associated with higher TFR rates.” (Discover Oncology, 2024) (zheng2024treatmentfreeremissionafter pages 1-3, zheng2024treatmentfreeremissionafter pages 8-12)

Concluding perspective CML pathophysiology is anchored in BCR-ABL1–driven oncogenic signaling (STAT5, RAS/MAPK, PI3K/AKT) and sustained by LSCs protected through bone marrow niche signals and metabolic dependencies, notably OXPHOS and pyruvate anaplerosis. Contemporary data implicate the niche cytokine CXCL14 as a suppressor of LSC mTOR/OXPHOS programs, suggest metabolic co-targeting (e.g., MPC inhibition) to eliminate persistent LSCs, and underscore immune correlates (NK phenotypes, PD-1/PD-L1 axes) in TFR durability. Progression frequently tracks with ASXL1, RUNX1, IKZF1 and TP53 lesions and acquisition of additional cytogenetic abnormalities. Clinically, standardized MRD (qPCR IS) and increasingly dPCR, together with DMR depth/duration and selected clinical and immunologic predictors, enable rational TFR attempts within guideline frameworks (ELN 2025). (sicuranza2025thebiologyof pages 1-2, dolinska2023characterizationofthe pages 14-26, rinaldi2023chronicmyeloidleukemia pages 2-4, patterson2023thebonemarrow pages 1-2, pratiwi2025geneticprofilingof pages 23-24, zheng2024treatmentfreeremissionafter pages 1-3, rinaldi2023chronicmyeloidleukemia pages 13-14)

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