Wee1 promotes cell proliferation and imatinib resistance in chronic myeloid leukemia via regulating DNA damage repair dependent on ATM-γH2AX-MDC1

Cell Communication and Signaling

Research

Fanting Zeng¹  Guoyun Jiang¹  Yuhang Peng¹  Yuefeng Qin¹  Jianming Wang¹  Wenli Feng¹  Ying Yuan² 

[1] Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, 400016, Chongqing, China;Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, 400016, Chongqing, China;

关键词: Chronic myeloid leukemia;    Wee1;    DNA damage repair;    DNA damage response;   

DOI  :  10.1186/s12964-022-01021-z

 received in 2022-11-11, accepted in 2022-12-14,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe treatment of chronic myeloid leukemia (CML) is facing the dilemma of tyrosine kinase inhibitors (TKIs) resistance and disease recurrence. The dysfunctional DNA damage repair mechanism plays an essential role not only in the initiation and progression of hematological malignancies but also links to the development of TKI resistance. Deciphering the abnormally regulated DNA damage repair and proteins involved brings new insights into the therapy of leukemias. As a G2/M phase checkpoint kinase and a DNA damage repair checkpoint kinase engaged in the DNA damage response (DDR), along with an oncogenic driver present in various cancers, the particular involvement of Wee1 in DNA damage is far from clear. Deciphering its function and targeting it via modulating DNA repair pathways is important for improving our understanding of cancer treatment.MethodsWee1 expression was assessed in cell lines using RT-qPCR and western blot, and Wee1 knockdown efficacy was validated using RT-qPCR, western blot, and immunofluorescence. Wee1 function was investigated by CCK-8, colony formation, and flow cytometry assay in vitro. Wee1 role in DNA repair and its interactions with other proteins were then studied using western blot, immunofluorescence, and double plasmid-repair studies. Finally, the CCK-8 and flow cytometry assay was utilized to investigate Wee1 and imatinib’s synergistic effect, and a CML mouse model was constructed to study Wee1’s role in carcinogenesis in vivo.ResultsWee1 was reported to respond quickly to DDR in an ATM-γH2AX-MDC1-dependent way upon DNA double-strand breaks (DSBs) occurrence, and it regulated homologous recombination by stimulating the recruitment of critical proteins RAD51/BRCA1 upon DSB sites. Wee1 was also revealed to be abnormally upregulated in CML cells. Further suppression of Wee1 not only causes cell cycle arrest and inhibits the proliferation of cancer cells but also enhances CML cell sensitivity to Imatinib in vitro and in vivo, possibly through an excessive accumulation of overall DSBs.ConclusionWee1 is extensively involved in the DRR signaling and DSB repair pathway. Inhibiting abnormally elevated Wee1 benefits CML therapy in both IM-resistant and IM-sensitive cells. Our data demonstrated that Wee1 participated in promoting cell proliferation and imatinib resistance in chronic myeloid leukemia via regulating DNA damage repair dependent on ATM-γH2AX-MDC1. In the fight against CML, Wee1’s dysregulation in the DNA damage repair mechanism of CML pathogenesis makes it a viable therapeutic target in clinical applications.

【 授权许可】

CC BY   
© The Author(s) 2022

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