Breakpoint cluster region–Abelson murine leukemia viral oncogene 1 fusion protein and SRC family kinase (BCR-ABL1 (for the fusion protein); SFKs (for SRC family kinases))

The BCR-ABL1 fusion protein is a constitutively active tyrosine kinase generated by the reciprocal translocation t(9;22)—the Philadelphia chromosome—fusing the BCR gene on chromosome 22 to the ABL1 gene on chromosome 9. This fusion generates a chimeric protein with deregulated kinase activity that drives leukemogenesis by promoting proliferation, blocking apoptosis, and inducing genetic instability. It activates several downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and JAK/STAT, as well as interacting with and amplifying SRC family kinase signaling. The SRC family kinases (such as LYN, FYN, HCK) are non-receptor tyrosine kinases which can further amplify oncogenic signaling and have been implicated in resistance to tyrosine kinase inhibitor therapy. Targeting BCR-ABL1, and in some advanced phases, targeting SRC kinases as well, is the main therapeutic approach for Philadelphia chromosome–positive leukemias, especially chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia.

Other names

Philadelphia chromosome fusion proteinBCR-ABL fusion proteinPh+ fusion proteinSFKsSRC kinasesSRCLYNHCKFYN

ATP-competitive inhibition of the BCR-ABL1 tyrosine kinase activity. Dual inhibition of BCR-ABL1 and SRC family kinases (some TKIs, e.g. dasatinib).