1. Academic Validation
  2. Inhibition of LATS kinases reduces tumorigenicity and increases the sensitivity of human chronic myelogenous leukemia cells to imatinib

Inhibition of LATS kinases reduces tumorigenicity and increases the sensitivity of human chronic myelogenous leukemia cells to imatinib

  • Sci Rep. 2024 Feb 18;14(1):3993. doi: 10.1038/s41598-024-54728-z.
Phatchanat Klaihmon 1 Chanchao Lorthongpanich 2 3 Pakpoom Kheolamai 4 Wannachai Saisaard 5 Surapol Issaragrisil 1 5
Affiliations

Affiliations

  • 1 Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
  • 2 Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. chanchao.cl@gmail.com.
  • 3 Blood Products and Cellular Immunotherapy Research Group, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand. chanchao.cl@gmail.com.
  • 4 Center of Excellence in Stem Cell Research and Innovations, Division of Cell Biology, Faculty of Medicine, Thammasat University, Pathumthani, Thailand. pkheolamai@me.com.
  • 5 Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Abstract

Chronic myelogenous leukemia (CML) is a clonal hematologic malignancy of the myeloid lineage caused by the oncogenic BCR/ABL fusion protein that promotes CML cell proliferation and protects them against drug-induced Apoptosis. In this study, we determine LATS1 and LATS2 expression in CML cells derived from patients who are resistant to imatinib (IM) treatment. Significant upregulation of LATS1 and LATS2 was found in these CML patients compared to healthy donors. To further explore whether the expression of LATS1/2 contributes to the IM-resistant phenotype, IM-resistant CML cell lines generated by culturing CML-derived erythroblastic K562 cells in increasing concentrations of IM were used as in vitro models. Up-regulation of LATS1 and LATS2 was observed in IM-resistant K562 cells. Reduction of LATS using either Lats-IN-1 (TRULI), a specific LATS inhibitor, or shRNA targeting LATS1/2 significantly reduced clonogenicity, increased Apoptosis and induced differentiation of K562 cells to late-stage erythroid cells. Furthermore, depletion of LATS1 and LATS2 also increased the sensitivity of K562 cells to IM. Taken together, our results suggest that LATS could be one of the key factors contributing to the rapid proliferation, reduced Apoptosis, and IM resistance of CML cells. Targeting LATS could be a promising treatment to enhance the therapeutic effect of a conventional BCR/ABL tyrosine kinase inhibitor such as IM.

Keywords

Apoptosis; Chronic myelogenous leukemia; Hippo pathway; Imatinib; LATS kinase.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-138489
    99.98%, Lat1/2 kinases Inhibitor
    YAP