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MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents

Oncogene volume 35, pages 5905–5915 (2016)Cite this article

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Abstract

MMSET/WHSC1 is a histone methyltransferase (HMT) overexpressed in t(4;14)+ multiple myeloma (MM) patients, believed to be the driving factor in the pathogenesis of this MM subtype. MMSET overexpression in MM leads to an increase in histone 3 lysine 36 dimethylation (H3K36me2), and a decrease in histone 3 lysine 27 trimethylation (H3K27me3), as well as changes in proliferation, gene expression and chromatin accessibility. Prior work linked methylation of histones to the ability of cells to undergo DNA damage repair. In addition, t(4;14)+ patients frequently relapse after regimens that include DNA damage-inducing agents, suggesting that MMSET may play a role in DNA damage repair and response. In U2OS cells, we found that MMSET is required for efficient non-homologous end joining as well as homologous recombination. Loss of MMSET led to loss of expression of several DNA repair proteins, as well as decreased recruitment of DNA repair proteins to sites of DNA double-strand breaks (DSBs). By using genetically matched MM cell lines that had either high (pathological) or low (physiological) expression of MMSET, we found that MMSET-high cells had increased damage at baseline. Upon addition of a DNA-damaging agent, MMSET-high cells repaired DNA damage at an enhanced rate and continued to proliferate, whereas MMSET-low cells accumulated DNA damage and entered cell cycle arrest. In a murine xenograft model using t(4;14)+ KMS11 MM cells harboring an inducible MMSET shRNA, depletion of MMSET enhanced the efficacy of chemotherapy, inhibiting tumor growth and extending survival. These findings help explain the poorer prognosis of t(4;14) MM and further validate MMSET as a potential therapeutic target in MM and other cancers.

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Acknowledgements

This study was supported by NIH grant R01CA123204, Leukemia & Lymphoma Society Specialized Center for Research Award, Physical Sciences Oncology Center U54CA143869, Celgene and the Samuel Waxman Cancer Research Foundation (to JDL); NIH grants R01CA174388 and U54CA143868 (to DW); and Canadian Institute of Health and Research operating grant (287300; to NJB). We thank Dr Gaëlle Legube for the AsiSI-U2OS cells and members of the Licht lab for their helpful comments.

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  1. M Y Shah and E Martinez-Garcia: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    M Y Shah, E Martinez-Garcia, R Popovic, T Ezponda, E C Small, C Will & J D Licht

  2. Department of Chemical and Biomolecular Engineering, Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD, USA

    J M Phillip, A B Chambliss, M P Phillip & D Wirtz

  3. Departments of Oncology and Medicine, University of Calgary and Tom Baker Cancer Centre, Calgary, AB, Canada

    P Neri & N J Bahlis

  4. Department of Oncology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D Wirtz

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JDL receives funding from Celgene.

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Shah, M., Martinez-Garcia, E., Phillip, J. et al. MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents. Oncogene 35, 5905–5915 (2016). https://doi.org/10.1038/onc.2016.116

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