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Myeloma

Evidence for ongoing DNA damage in multiple myeloma cells as revealed by constitutive phosphorylation of H2AX

Leukemia volume 25, pages 1344–1353 (2011)Cite this article

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Abstract

DNA double-strand breaks (DSBs) are deleterious lesions that can lead to chromosomal anomalies, genomic instability and cancer. The histone protein H2AX has an important role in the DNA damage response (DDR) and the presence of phospho-H2AX (γH2AX) nuclear foci is the hallmark of DSBs. We hypothesize that ongoing DNA damage provides a mechanism by which chromosomal abnormalities and intratumor heterogeneity are acquired in malignant plasma cells (PCs) in patients with multiple myeloma (MM). Therefore, we assessed PCs from patients with the premalignant condition, monoclonal gammopathy of undetermined significance (MGUS) and MM, as well as human MM cell lines (HMCLs) for evidence of DSBs. γH2AX foci were detected in 2/5 MGUS samples, 37/40 MM samples and 6/6 HMCLs. Notably, the DSB response protein 53BP1 colocalized with γH2AX in both MM patient samples and HMCLs. Treatment with wortmannin decreased phosphorylation of H2AX and suggests phosphoinositide (PI) 3-kinases and/or PI3-kinase-like family members underlie the presence of γH2AX foci in MM cells. Taken together, these data imply that ongoing DNA damage intensifies across the disease spectrum of MGUS to MM and may provide a mechanism whereby clonal evolution occurs in the monoclonal gammopathies.

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Acknowledgements

This work was supported by a grant from the National Institutes of Health (CA062242).

Author contributions

DKW designed and performed research, analyzed data and wrote the manuscript. RCT, BKA and KJH performed research and analyzed data. XW designed research and interpreted data. PMH and AD designed research and enrolled patients. DFJ designed research, wrote and approved the manuscript.

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Authors and Affiliations

  1. Department of Immunology, Mayo Clinic, College of Medicine, Rochester, MN, USA

    D K Walters, X Wu, R C Tschumper, B K Arendt & D F Jelinek

  2. Department of Orthopedic Surgery, Mayo Clinic, College of Medicine, Rochester, MN, USA

    P M Huddleston

  3. Department of Internal Medicine, Mayo Clinic, College of Medicine, Rochester, MN, USA

    K J Henderson & A Dispenzieri

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  1. D K Walters
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Correspondence to D F Jelinek.

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Walters, D., Wu, X., Tschumper, R. et al. Evidence for ongoing DNA damage in multiple myeloma cells as revealed by constitutive phosphorylation of H2AX. Leukemia 25, 1344–1353 (2011). https://doi.org/10.1038/leu.2011.94

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