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

BCR-ABL1 is a constitutively active tyrosine kinase resulting from the Philadelphia chromosome translocation, t(9;22)(q34;q11), which fuses the BCR gene with the ABL1 tyrosine kinase gene (Source: National Cancer Institute). This fusion protein is the primary driver of Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL), promoting cell survival and proliferation through pathways such as PI3K/AKT and RAS/MAPK (Source: Apperley, J. F., Lancet, 2015). The T315I mutation is a specific gatekeeper mutation where threonine is replaced by isoleucine at position 315 in the ABL1 kinase domain. This mutation eliminates a critical hydrogen bond and creates steric hindrance, rendering the protein resistant to most standard tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib (Source: Huang, W. S., et al., J. Med. Chem., 2010). Ba/F3 cells expressing this mutant are frequently used as an in vitro model to screen for new inhibitors capable of overcoming this resistance. Third-generation TKIs like ponatinib and allosteric inhibitors like asciminib have been developed to specifically target the T315I mutant, providing therapeutic options for patients with resistant disease (Source: Hughes, T. P., et al., NEJM, 2019).

Other names

BCR-ABL T315IT315I mutant BCR-ABLGatekeeper mutation BCR-ABLp210 BCR-ABL T315IPhiladelphia chromosome protein T315I mutant

Inhibition of the BCR-ABL1 tyrosine kinase activity through ATP-competitive binding (e.g., ponatinib) or allosteric binding to the myristoyl pocket (e.g., asciminib).