Molecular characterization of ABL kinase domain mutations associated with imatinib resistance in chronic myeloid leukemia patients, including a novel pathogenic D276V variant.

Abstract

e18598 Background: Imatinib resistance in chronic myeloid leukemia (CML) is frequently driven by BCR-ABL–dependent mechanisms, particularly mutations in the ABL tyrosine kinase domain that can disrupt imatinib binding, creating a need for early mutation screening to guide treatment adaptation. Methods: We conducted molecular monitoring by qRT-PCR in 90 CML patients and performed Sanger sequencing of the ABL kinase domain in patients who did not achieve molecular remission. Results: Out of 90 patients, 22 lacked molecular remission; among these, 7 patients harbored resistance-associated mutations in the BCR-ABL transcript. The detected mutations included T315I (57%), E255V (29%), and a case with G250E plus an additional D276V variant. Bioinformatics analyses supported D276V as a novel pathogenic mutation. (The patient with G250E+D276V subsequently died). Conclusions: In this cohort, ABL kinase domain mutations were identified in a subset of patients with absent molecular remission on imatinib, supporting the clinical value of early mutational profiling to inform therapeutic adjustment.