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

The BCR-ABL1 T315I mutant is a variant of the BCR-ABL1 fusion protein, which is the primary driver of Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) [1, 4]. This fusion protein results from the reciprocal translocation t(9;22) and exhibits constitutive tyrosine kinase activity, leading to uncontrolled cell proliferation and survival [3, 6]. The T315I mutation, often referred to as the gatekeeper mutation, involves a threonine-to-isoleucine substitution at position 315 in the ABL kinase domain [1, 9]. This specific alteration creates steric hindrance and removes a critical hydrogen bond, rendering the protein resistant to most first- and second-generation tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib [2, 8]. Therapeutic strategies to target this mutant include third-generation TKIs like ponatinib, which can accommodate the bulky isoleucine residue, and allosteric inhibitors like asciminib, which bind to the myristoyl pocket [9, 10]. Monitoring for the T315I mutation is a critical component of clinical management for patients who fail initial TKI therapy [12].

Other names

T315I mutationGatekeeper mutationBCR-ABL1(T315I)p210 BCR-ABL T315Ip185 BCR-ABL T315I

ATP-competitive inhibition of the ABL kinase domain and allosteric inhibition via the myristoyl pocket (STAMP mechanism) [1, 9, 10].