Biological Features of KLC2 Mutations in Chronic Myeloid Leukemia and Their Contribution to Inducing Drug Resistance.

[BACKGROUND] Breakpoint Cluster Region-Abelson (BCR::ABL1) fusion protein is essential in the pathogenesis of chronic myeloid leukemia (CML); however, the chronic-to-blast phase transformation remains elusive. We identified novel kinesin light chain 2 () mutations in CML-myeloid blast phase patients. We aimed to examine the functional role of mutations in leukemogenesis.

[METHODS] To evaluate the biological role of KLC2 mutants (MT) in CML cells, we expressed in different human CML cell lines harboring and performed immunoblot, immunofluorescence, cell proliferation, differentiation, and apoptosis; Tyrosine kinase inhibitor (TKI)-drug activities; and clonogenic assays for functional analyses. We co-expressed and in mouse bone marrow cells (BMCs) to evaluate their clonogenic and self-renewal abilities . Furthermore, we examined tumorigenic activity and drug efficacy in the K562 xenograft model.

[RESULTS] overexpression in positive K562 and KU812 CML cells promoted cell proliferation and clonogenic potential, decreased imatinib sensitivity, and reduced apoptosis. Serial colony replating assays revealed that KLC2-MT and BCR::ABL1 co-expression enhanced the self-renewal ability of mouse BMCs with immature morphology. In the K562 xenograft model, KLC2-MT enhanced tumorigenic potential and diminished imatinib efficacy. Further studies reported that KLC2-MT augmented signal transducer and activator of transcription 3 (STAT3) activation and nuclear accumulation in imatinib-treated CML cells. KLC2-WT and KLC2-MT interacted with mothers against decapentaplegic homolog 2 (SMAD2); however, the latter impaired transforming growth factor-beta (TGF-β)-mediated SMAD2/3 activation while enhancing STAT3 phosphorylation.

[CONCLUSIONS] This study demonstrates the biological and functional importance of KLC2 mutation in CML cells, potentially enabling the development of better treatment strategies for CML patients carrying mutations and providing enhanced understanding of the disease progression.