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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name: Chronic Myeloid Leukemia, BCR-ABL1 Positive
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-11T02:45:15Z'
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.
- 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.
- 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: PARTIAL
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
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
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
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
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
histopathology:
- name: Philadelphia Chromosome Positive Neoplasm
finding_term:
preferred_term: B Acute Lymphoblastic Leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1
term:
id: NCIT:C36312
label: B Acute Lymphoblastic Leukemia with t(9;22)(q34.1;q11.2); BCR-ABL1
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
- 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
- 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
- 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
- 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
- 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
- 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
biochemical:
- name: Philadelphia Chromosome Detection
notes: >-
Cytogenetic analysis reveals t(9;22)(q34;q11) translocation creating the
Philadelphia chromosome in 95% of CML cases.
- 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.
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: PARTIAL
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
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
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)
- name: Nilotinib
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
- name: Ponatinib
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: PARTIAL
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: PARTIAL
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: hematopoietic stem cell transplantation
term:
id: MAXO:0000747
label: hematopoietic stem cell transplantation
disease_term:
preferred_term: chronic myeloid leukemia
term:
id: MONDO:0011996
label: chronic myelogenous leukemia, BCR-ABL1 positive
classifications:
icdo_morphology:
classification_value: Leukemia
harrisons_chapter:
- classification_value: cancer
- classification_value: hematologic malignancy
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)
References
(dolinska2023characterizationofthe pages 14-26): Monika Dolinska, Huan Cai, Alma Mansson, Jingyi Shen, Pingnan Xiao, Thibault Bouderlique, Xidan Li, Elory Leonard, Marcus Chang, Yuchen Gao, Juan Pablo Medina Giménez, Makoto Kondo, Lakshmi Sandhow, Anne-Sofie Johansson, Stefan Deneberg, Stina Söderlund, Martin Jädersten, Johanna S Ungerstedt, Magnus Tobiasson, Arne Östman, Satu Mustjoki, Leif Stenke, Katarina Le Blanc, Eva S Hellstrom-Lindberg, Sören Lehmann, Marja Ekblom, Ulla Olsson-Strömberg, Mikael Sigvardsson, and Hong Qian. Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies cxcl14 as a new therapeutic option. Blood, 142:73-89, Apr 2023. URL: https://doi.org/10.1182/blood.2022016896, doi:10.1182/blood.2022016896. This article has 24 citations and is from a highest quality peer-reviewed journal.
(rinaldi2023chronicmyeloidleukemia pages 2-4): Ikhwan Rinaldi and Kevin Winston. Chronic myeloid leukemia, from pathophysiology to treatment-free remission: a narrative literature review. Journal of Blood Medicine, 14:261-277, Apr 2023. URL: https://doi.org/10.2147/jbm.s382090, doi:10.2147/jbm.s382090. This article has 86 citations.
(patterson2023thebonemarrow pages 1-2): Shaun David Patterson and Mhairi Copland. The bone marrow immune microenvironment in cml: treatment responses, treatment-free remission, and therapeutic vulnerabilities. Current Hematologic Malignancy Reports, 18:19-32, Feb 2023. URL: https://doi.org/10.1007/s11899-023-00688-6, doi:10.1007/s11899-023-00688-6. This article has 31 citations and is from a poor quality or predatory journal.
(zheng2024treatmentfreeremissionafter pages 1-3): Zhenxiang Zheng, Hao Tang, Xinxia Zhang, Liling Zheng, Zhao Yin, Jie Zhou, and Yang-min Zhu. Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis. Discover Oncology, Oct 2024. URL: https://doi.org/10.1007/s12672-024-01444-9, doi:10.1007/s12672-024-01444-9. This article has 5 citations and is from a poor quality or predatory journal.
(rinaldi2023chronicmyeloidleukemia pages 13-14): Ikhwan Rinaldi and Kevin Winston. Chronic myeloid leukemia, from pathophysiology to treatment-free remission: a narrative literature review. Journal of Blood Medicine, 14:261-277, Apr 2023. URL: https://doi.org/10.2147/jbm.s382090, doi:10.2147/jbm.s382090. This article has 86 citations.
(sicuranza2025thebiologyof pages 1-2): Anna Sicuranza, Alessia Cavalleri, and Simona Bernardi. The biology of chronic myeloid leukemia: an overview of the new insights and biomarkers. Frontiers in Oncology, May 2025. URL: https://doi.org/10.3389/fonc.2025.1546813, doi:10.3389/fonc.2025.1546813. This article has 10 citations and is from a poor quality or predatory journal.
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(pratiwi2025geneticprofilingof pages 23-24): Laras Pratiwi, Fawzia Hanum Mashudi, Mukti Citra Ningtyas, Henry Sutanto, and Pradana Zaky Romadhon. Genetic profiling of acute and chronic leukemia via next-generation sequencing: current insights and future perspectives. Hematology Reports, 17:18, Mar 2025. URL: https://doi.org/10.3390/hematolrep17020018, doi:10.3390/hematolrep17020018. This article has 10 citations and is from a poor quality or predatory journal.
(patterson2023thebonemarrow pages 2-5): Shaun David Patterson and Mhairi Copland. The bone marrow immune microenvironment in cml: treatment responses, treatment-free remission, and therapeutic vulnerabilities. Current Hematologic Malignancy Reports, 18:19-32, Feb 2023. URL: https://doi.org/10.1007/s11899-023-00688-6, doi:10.1007/s11899-023-00688-6. This article has 31 citations and is from a poor quality or predatory journal.
(patterson2023thebonemarrow pages 5-6): Shaun David Patterson and Mhairi Copland. The bone marrow immune microenvironment in cml: treatment responses, treatment-free remission, and therapeutic vulnerabilities. Current Hematologic Malignancy Reports, 18:19-32, Feb 2023. URL: https://doi.org/10.1007/s11899-023-00688-6, doi:10.1007/s11899-023-00688-6. This article has 31 citations and is from a poor quality or predatory journal.
(pratiwi2025geneticprofilingof pages 24-25): Laras Pratiwi, Fawzia Hanum Mashudi, Mukti Citra Ningtyas, Henry Sutanto, and Pradana Zaky Romadhon. Genetic profiling of acute and chronic leukemia via next-generation sequencing: current insights and future perspectives. Hematology Reports, 17:18, Mar 2025. URL: https://doi.org/10.3390/hematolrep17020018, doi:10.3390/hematolrep17020018. This article has 10 citations and is from a poor quality or predatory journal.
(гордіичук2025precisionmonitoringin pages 3-5): П. І. Гордійчук, Д. В. Мельник, M. P. Гордійчук, and О. В. Калачов. Precision monitoring in chronic myeloid leukemia: digital pcr and quantitative rt-pcr for predicting stable deep molecular response and treatment-free remission. Likarska sprava, Dec 2025. URL: https://doi.org/10.31640/ls-2025-4-29, doi:10.31640/ls-2025-4-29. This article has 0 citations.
(zheng2024treatmentfreeremissionafter pages 8-12): Zhenxiang Zheng, Hao Tang, Xinxia Zhang, Liling Zheng, Zhao Yin, Jie Zhou, and Yang-min Zhu. Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis. Discover Oncology, Oct 2024. URL: https://doi.org/10.1007/s12672-024-01444-9, doi:10.1007/s12672-024-01444-9. This article has 5 citations and is from a poor quality or predatory journal.
(lagana2025treatmentfreeremission pages 1-2): Alessandro Laganà, Emilia Scalzulli, Ida Carmosino, Maria Laura Bisegna, Claudia Ielo, Daniela Diverio, Maurizio Martelli, and Massimo Breccia. Treatment free remission (tfr) in chronic phase-chronic myeloid leukemia (cp-cml): analysis of predictive factors and novel baseline scoring system to predict molecular relapse. European journal of haematology, Jun 2025. URL: https://doi.org/10.1111/ejh.70006, doi:10.1111/ejh.70006. This article has 3 citations and is from a peer-reviewed journal.
(rinaldi2023chronicmyeloidleukemia pages 8-9): Ikhwan Rinaldi and Kevin Winston. Chronic myeloid leukemia, from pathophysiology to treatment-free remission: a narrative literature review. Journal of Blood Medicine, 14:261-277, Apr 2023. URL: https://doi.org/10.2147/jbm.s382090, doi:10.2147/jbm.s382090. This article has 86 citations.
(zheng2024treatmentfreeremissionafter pages 12-13): Zhenxiang Zheng, Hao Tang, Xinxia Zhang, Liling Zheng, Zhao Yin, Jie Zhou, and Yang-min Zhu. Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis. Discover Oncology, Oct 2024. URL: https://doi.org/10.1007/s12672-024-01444-9, doi:10.1007/s12672-024-01444-9. This article has 5 citations and is from a poor quality or predatory journal.