Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 mutant kinase (BCR-ABL1 mutant)

BCR-ABL1 mutant kinase refers to the oncogenic fusion protein BCR-ABL1 that has acquired secondary point mutations, typically within the kinase domain, leading to resistance against standard tyrosine kinase inhibitors (TKIs) [1, 10]. The primary BCR-ABL1 fusion results from the Philadelphia chromosome translocation t(9;22), which creates a constitutively active tyrosine kinase that drives the pathogenesis of Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) [4, 12]. Mutations such as the T315I gatekeeper mutation disrupt the binding of traditional ATP-competitive inhibitors like imatinib, necessitating the use of third-generation TKIs like ponatinib or allosteric inhibitors like asciminib [5, 11]. These mutant kinases continue to activate downstream signaling pathways, including PI3K/Akt, STAT5, and Ras/MAPK, to promote leukemic cell survival and uncontrolled proliferation [4, 13]. Monitoring these mutations via molecular testing is critical for managing treatment-resistant leukemia and selecting appropriate salvage therapies [1, 10].

Other names

BCR-ABL1 fusion protein mutantPhiladelphia chromosome mutant kinaseT315I BCR-ABL1p210 BCR-ABL1 mutantp190 BCR-ABL1 mutantABL1 mutant

Tyrosine kinase inhibition via ATP-competitive binding or allosteric modulation of the myristoyl pocket