Open Access

ARTICLE

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

Rabindranath Bera^1,#, Yotaro Ochi^2,3, Ying-Jung Huang¹, Ming-Chung Kuo^1,4, Kenichi Yoshida⁵, Seishi Ogawa², Lee-Yung Shih^1,4,*

1 Division of Hematology-Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan City, 333, Taiwan
2 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, 6068501, Japan
3 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 6068501, Japan
4 School of Medicine, Chang Gung University, Taoyuan City, 333, Taiwan
5 Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, 1040045, Japan

* Corresponding Author: Lee-Yung Shih. Email:
# Current Address: Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan City, 33302, Taiwan

(This article belongs to the Special Issue: New Insights in Drug Resistance of Cancer Therapy: A New Wine in an Old Bottle)

Oncology Research 2026, 34(1), . https://doi.org/10.32604/or.2025.070259

Received 11 July 2025; Accepted 30 October 2025; Issue published 30 December 2025

Abstract

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 (KLC2) mutations in CML-myeloid blast phase patients. We aimed to examine the functional role of KLC2 mutations in leukemogenesis. Methods: To evaluate the biological role of KLC2 mutants (MT) in CML cells, we expressed KLC2-MT in different human CML cell lines harboring BCR::ABL1 and performed immunoblot, immunofluorescence, cell proliferation, differentiation, and apoptosis; Tyrosine kinase inhibitor (TKI)-drug activities; and clonogenic assays for in vitro functional analyses. We co-expressed KLC2-MT and BCR::ABL1 in mouse bone marrow cells (BMCs) to evaluate their clonogenic and self-renewal abilities ex vivo. Furthermore, we examined tumorigenic activity and drug efficacy in the K562 xenograft model. Results: KLC2-MT overexpression in BCR::ABL1-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 KLC2 mutations and providing enhanced understanding of the disease progression.

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Supplementary Material

Supplementary Material File

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