@Article{or.2025.070259,
AUTHOR = {Rabindranath Bera, Yotaro Ochi, Ying-Jung Huang, Ming-Chung Kuo, Kenichi Yoshida, Seishi Ogawa, Lee-Yung Shih},
TITLE = {Biological Features of KLC2 Mutations in Chronic Myeloid Leukemia and Their Contribution to Inducing Drug Resistance},
JOURNAL = {Oncology Research},
VOLUME = {34},
YEAR = {2026},
NUMBER = {1},
PAGES = {0--0},
URL = {http://www.techscience.com/or/v34n1/65184},
ISSN = {1555-3906},
ABSTRACT = { <b>Background:</b> 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 (<i>KLC2</i>) mutations in CML-myeloid blast phase patients. We aimed to examine the functional role of <i>KLC2</i> mutations in leukemogenesis. <b>Methods:</b> To evaluate the biological role of KLC2 mutants (MT) in CML cells, we expressed <i>KLC2-MT</i> in different human CML cell lines harboring <i>BCR::ABL1</i> and performed immunoblot, immunofluorescence, cell proliferation, differentiation, and apoptosis; Tyrosine kinase inhibitor (TKI)-drug activities; and clonogenic assays for <i>in vitro</i> functional analyses. We co-expressed <i>KLC2-MT</i> and <i>BCR::ABL1</i> in mouse bone marrow cells (BMCs) to evaluate their clonogenic and self-renewal abilities <i>ex vivo</i>. Furthermore, we examined tumorigenic activity and drug efficacy in the K562 xenograft model. <b>Results:</b> <i>KLC2-MT</i> overexpression in <i>BCR::ABL1-</i>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. <b>Conclusions:</b> 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 <i>KLC2</i> mutations and providing enhanced understanding of the disease progression.},
DOI = {10.32604/or.2025.070259}
}