Abelson murine leukemia viral oncogene homolog 1 T315I mutant (ABL1 T315I) (ABL1 T315I)

The ABL1 T315I mutant is a clinically significant variant of the Abelson murine leukemia viral oncogene homolog 1 (ABL1) protein, primarily occurring within the BCR-ABL1 fusion oncoprotein [2, 4]. This "gatekeeper" mutation involves the substitution of threonine with isoleucine at position 315 in the kinase domain, which eliminates a critical hydrogen bond and creates steric hindrance that prevents the binding of first- and second-generation tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, and nilotinib [1, 2, 13]. Consequently, the mutant protein remains constitutively active, driving the dysregulated signaling pathways that lead to uncontrolled cell proliferation and survival in hematopoietic cells [2, 11]. This mutation is a major cause of therapeutic failure and disease progression in patients with Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) [4, 14, 17]. To address this resistance, specialized drugs have been developed, including third-generation TKIs like ponatinib and allosteric inhibitors like asciminib, which target the protein through alternative binding sites [4, 5, 13]. Detection of the T315I mutation via PCR or sequencing is a vital biomarker for guiding treatment selection and monitoring for drug resistance in clinical practice [16, 18, 19]. Therapeutic challenges include the emergence of compound mutations and severe safety concerns such as vascular occlusion associated with certain potent inhibitors [4, 5, 8].

Other names

BCR-ABL1 T315IGatekeeper mutation T315IThr315Ile mutantp.Thr315IleBCR-ABL T315I

Tyrosine kinase inhibition, Allosteric inhibition, Protein synthesis inhibition