Breakpoint cluster region–Abelson tyrosine kinase fusion protein (BCR-ABL)

The Breakpoint cluster region–Abelson tyrosine kinase fusion protein (BCR-ABL) is a constitutively active fusion tyrosine kinase produced by a reciprocal chromosomal translocation, t(9;22)(q34;q11), known as the Philadelphia chromosome, which fuses the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. The BCR-ABL fusion protein localizes to the cytoplasm, bypassing normal regulatory controls and resulting in deregulated, persistent tyrosine kinase activity that drives abnormal cell proliferation, survival, and resistance to apoptosis, leading to the pathogenesis of chronic myeloid leukemia (CML) and other Philadelphia chromosome-positive leukemias. BCR-ABL serves as the molecular target for tyrosine kinase inhibitors (TKIs), such as imatinib and its successors, which inhibit the ATP-binding site (or in the case of asciminib, the myristoyl pocket), disrupt oncogenic signaling, and have revolutionized the treatment and prognosis of CML, although resistance and long-term safety remain clinical challenges.

Other names

BCR-ABL1Philadelphia chromosome fusion proteinBcr-Abl fusion proteinPhiladelphia (Ph) chromosome-derived tyrosine kinaseBreakpoint cluster region–Abelson murine leukemia viral oncogene homolog 1 fusion protein

ATP-competitive inhibition of kinase activity (imatinib, nilotinib, dasatinib, bosutinib, ponatinib); Allosteric inhibition via myristoyl pocket binding (asciminib); Induction of inactive kinase conformation, preventing substrate phosphorylation