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Targeting MDC1 promotes apoptosis and sensitizes Imatinib resistance in CML cells by mainly disrupting non-homologous end-joining repair

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Abstract

The first-line drug Imatinib (IM) has achieved a curative effect in most chronic myeloid leukemia (CML) patients, but drug resistance remains a problem. More alternative therapeutic strategies need to explore. In recent years, targeting dysregulated DNA repair mechanisms provided promising options for cancer treatment. Here, we discovered the versatile Mediator of DNA Damage Checkpoint 1 (MDC1) interacted with γ-H2AX and 53BP1 in the early stage of the DNA damage response of cells. MDC1 overexpressed in CML cell lines and patients’ bone marrow mononuclear cells. By knocking down MDC1, non-homologous end-joining pathways were mainly inhibited, leading to an intense accumulation of unrepaired intracellular DNA damage and an apparent cell apoptosis promotion. Notably, targeting MDC1 further enhanced drug sensitivity in IM-resistant CML cells. Our work revealed that MDC1 is a prospective target for CML treatment through regulating DNA damage repair mechanism, and also an alternative option for IM resistance dilemma. This study extends the understanding of regulating dysfunctional DNA repair mechanisms for cancer treatment.

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Acknowledgements

We appreciate Dr.Yonghong Wang and Dr.Yalin Zhu for their assistance with experiments. Dr. Chen of the Radiology Department in the First Affiliated Hospital of Chongqing Medical University for the radiology support.

Funding

This work is supported by the National Natural Science Foundation of China (Grant No. 81703095), Chongqing Natural Science Foundation (Grant No. cstc2021jcyj-msxmX0214), Youth Top Science and Technology Talent Fund Project of The First Affiliated Hospital of Chongqing Medical University (Grant No. BJRC2020–04), and Innovation Support Program for Overseas Students of Chongqing (Grant No. cx2018142).

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Author notes

  1. Yang Liang and Yuefeng Qin have contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, Chongqing, China

    Yang Liang, Yuefeng Qin, Guoyun Jiang & Wenli Feng

  2. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Ying Yuan

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  1. Yang Liang
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Contributions

YY and YL conceived and designed the experiments. YL and YQ completed the experiments and wrote the draft. YL, YQ, WF, and YY analyzed the data and results. YY, WF, and GJ supervised the project and revised the manuscript. The final version of the manuscript was read and approved by all authors.

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Correspondence to Ying Yuan.

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The authors declare no competing interests.

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The research conformed to the standard stipulated by the Declaration of Helsinki and was performed with the approval of the Ethics Committee of Chongqing Medical University (ID:2022059).

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12032_2022_1821_MOESM2_ESM.tif

Supplementary file2 (TIF 5166 KB)—Figure S1. (A) Relativity mRNA expression of MDC1 in various cancer cells, data from CCLE datasets. (B) Network analysis of known protein interaction partners of MDC1, from STRING website. (C) Left. Abnormal large K562/G01 cells (200×); Right. enlarged cell image. (D, E) Cell viability was detected by the CCK-8 assay. Data are expressed as the mean ± SD.

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Liang, Y., Qin, Y., Jiang, G. et al. Targeting MDC1 promotes apoptosis and sensitizes Imatinib resistance in CML cells by mainly disrupting non-homologous end-joining repair. Med Oncol 39, 226 (2022). https://doi.org/10.1007/s12032-022-01821-w

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