Breakpoint cluster region–Abelson murine leukemia viral oncogene homolog 1 fusion protein tyrosine kinase (BCR-ABL1)

The BCR-ABL1 kinase is a constitutively active fusion protein resulting from a specific chromosomal translocation—t(9;22)(q34;q11)—that forms the Philadelphia chromosome. In this event, the N-terminal of the breakpoint cluster region (BCR) gene from chromosome 22 fuses with the C-terminal tyrosine kinase domain of the Abelson (ABL1) gene from chromosome 9, producing a chimeric oncoprotein with deregulated tyrosine kinase activity. BCR-ABL1 drives malignant transformation of hematopoietic cells through continuous activation of downstream signaling pathways involved in proliferation, inhibition of apoptosis, and escape from normal growth control mechanisms. It is the pathogenic hallmark and central therapeutic target for Philadelphia chromosome–positive leukemias, especially chronic myeloid leukemia (CML) and a portion of acute lymphoblastic leukemia (ALL). Selective inhibition of BCR-ABL1 with small-molecule tyrosine kinase inhibitors has dramatically improved patient outcomes, but resistance—especially via kinase domain mutations—remains a major clinical challenge. The most recognized BCR-ABL1 inhibitors include imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib. Monitoring BCR-ABL1 transcript levels serves as a key disease biomarker for therapy response and minimal residual disease tracking.

Other names

BCR-ABLBCR/ABL kinaseBCR-ABL fusion proteinPhiladelphia chromosome fusion proteinp210BCR-ABL (major isoform)p185BCR-ABL (minor isoform)c-ABL/BCR fusion

Inhibition of ATP binding to BCR-ABL1 kinase domain (competitive tyrosine kinase inhibition), downstream suppression of oncogenic signaling pathways