BCRABL1

BCR-ABL1 is a fusion gene created by the reciprocal translocation t(9;22)(q34;q11), known as the Philadelphia chromosome. The rearrangement merges part of the BCR gene on chromosome 22 with the ABL1 oncogene on chromosome 9, producing an in-frame BCR-ABL1 transcript that encodes an abnormal tyrosine kinase. Depending on the breakpoint within BCR and ABL1, the resulting protein variants are commonly referred to as p210, p190, or p230. The p210 form is most often associated with chronic myeloid leukemia (CML), while p190 is frequently linked to acute lymphoblastic leukemia (ALL); p230 is seen in a CML variant with slight differences in presentation.

Mechanistically, BCR-ABL1 exhibits constitutive tyrosine kinase activity, driving uncontrolled cell proliferation and resistance to apoptosis through multiple signaling pathways, including RAS/RAF/MEK/ERK, PI3K/AKT, and JAK/STAT. This signaling underlies the leukemogenic process and contributes to disease progression.

Clinical significance and detection involve identifying BCR-ABL1 via cytogenetics, fluorescence in situ hybridization (FISH), and molecular methods such as reverse-transcriptase polymerase chain reaction (RT-PCR) and quantitative RT-PCR to measure transcript levels. BCR-ABL1 is the defining abnormality in CML and is present in a substantial subset of ALL cases, particularly Philadelphia chromosome–positive ALL.

Therapeutically, BCR-ABL1 is the target of tyrosine kinase inhibitors (TKIs). Imatinib was the first widely used TKI, with subsequent agents including dasatinib, nilotinib, bosutinib, and ponatinib expanding options for resistant or intolerant cases. Molecular monitoring of BCR-ABL1 transcripts guides treatment decisions and helps assess response and relapse risk. Resistance can arise from kinase-domain mutations (e.g., T315I), BCR-ABL1 amplification, or alternative signaling mechanisms, necessitating therapy adjustments or transplantation in some cases.