BCR-ABL Gene Significance in Chronic Myeloid Leukemia
The BCR-ABL fusion gene is the pathogenic driver and diagnostic hallmark of CML, encoding a constitutively active tyrosine kinase protein that transforms hematopoietic stem cells and serves as the specific therapeutic target for tyrosine kinase inhibitors. 1
Molecular Pathogenesis
The BCR-ABL fusion gene results from the reciprocal translocation t(9;22)(q34;q11) between chromosomes 9 and 22, creating the Philadelphia chromosome 1. This genetic rearrangement produces an oncogenic fusion protein (most commonly p210BCR-ABL, less frequently p190 or p230) with three critical functional consequences 1:
- Constitutively activated tyrosine kinase activity that drives malignant transformation 1
- Attenuated DNA-protein binding activity of the ABL component 1
- Enhanced binding to cytoskeletal actin microfilaments 1
These molecular changes result in increased cellular proliferation, altered differentiation, and blocked apoptosis—the fundamental mechanisms underlying CML pathogenesis 1.
Diagnostic Significance
BCR-ABL detection is mandatory for CML diagnosis and must be demonstrated in patients with characteristic peripheral blood findings 2. The American Society of Hematology emphasizes that this fusion gene is the hallmark of CML 2.
Detection methods include:
- Conventional cytogenetics identifies the Philadelphia chromosome in 90-95% of cases at diagnosis 2
- FISH (fluorescence in situ hybridization) is mandatory when metaphases are insufficient or karyotype appears normal, to exclude cryptic rearrangements 2
- Qualitative RT-PCR identifies the specific BCR-ABL transcript type 2
Disease Progression and Genetic Instability
BCR-ABL-positive cells demonstrate inherent genetic instability, predisposing them to accumulate additional genomic abnormalities 1. This instability drives disease transformation from chronic phase through accelerated phase to blast crisis 1. The bulk of genetic changes occur during the transition from chronic to accelerated phase 1.
Point mutations in the BCR-ABL kinase domain represent a critical mechanism of disease progression and treatment resistance 1. These mutations were documented in 42% of chronic phase and 54% of accelerated phase patients after imatinib failure 3.
Therapeutic Target
The BCR-ABL protein is the specific molecular target of all tyrosine kinase inhibitors used in CML treatment 2. The identification of this fusion gene revolutionized CML therapy by enabling development of targeted agents including imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib 2, 4.
The oncogenic potential of BCR-ABL fusion proteins has been validated through their demonstrated ability to transform hematopoietic progenitor cells both in vitro and in vivo 1.
Prognostic and Monitoring Role
BCR-ABL transcript monitoring is essential for assessing treatment response and detecting disease progression 2. Treatment-free remission protocols require sustained molecular response defined as MR4.5 (BCR-ABL/ABL ≤ 0.0032% on International Scale) 3. Loss of major molecular response (MMR) triggers immediate treatment reinitiation 3.
The BCR-ABL/BCR transcript ratio may provide superior disease characterization compared to absolute BCR-ABL levels alone, particularly in non-responders 5.