Breakpoint cluster region–Abelson murine leukemia viral oncogene homolog 1 fusion protein, T315I mutant (BCR-ABL1 T315I)

The BCR-ABL1 T315I mutant is a fusion protein produced by the Philadelphia chromosome translocation, resulting in the juxtaposition of the BCR gene with the ABL1 gene. The T315I point mutation substitutes threonine for isoleucine at residue 315 in the ATP-binding site of ABL1, a position known as the "gatekeeper" residue. This mutation is clinically important because it confers broad resistance to first- and second-generation tyrosine kinase inhibitors used to treat chronic myeloid leukemia (CML) and some forms of acute lymphoblastic leukemia (ALL). The mutant maintains constitutive kinase activity, driving malignant cell proliferation and survival. Only select newer agents, such as ponatinib, asciminib, DCC-2036, pexmetinib, and omacetaxine, have clinical utility against this resistant variant. The T315I mutation remains a significant therapeutic challenge and a focus of ongoing drug development and monitoring efforts[1][2][3][4][6][7][8].

Other names

BCR-ABL T315IBCR::ABL1 T315IBCR-ABL1 gatekeeper mutantBCR-ABL1 kinase domain T315I mutant

Inhibition of BCR-ABL1 tyrosine kinase activity; Allosteric inhibition (asciminib targets myristoyl pocket); ATP-competitive inhibition (ponatinib, pexmetinib, DCC-2036); Protein synthesis inhibition (omacetaxine, not a kinase inhibitor but active against T315I mutant cells)