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Myeloma

MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC

Leukemia volume 27, pages 686–694 (2013)Cite this article

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Abstract

Multiple myeloma (MM) represents the malignant proliferation of terminally differentiated B cells, which, in many cases, is associated with the maintenance of high levels of the oncoprotein c-MYC. Overexpression of the histone methyltransferase MMSET (WHSC1/NSD2), due to t(4;14) chromosomal translocation, promotes the proliferation of MM cells along with global changes in chromatin; nevertheless, the precise mechanisms by which MMSET stimulates neoplasia remain incompletely understood. We found that MMSET enhances the proliferation of MM cells by stimulating the expression of c-MYC at the post-transcriptional level. A microRNA (miRNA) profiling experiment in t(4;14) MM cells identified miR-126* as an MMSET-regulated miRNA predicted to target c-MYC mRNA. We show that miR-126* specifically targets the 3′-untranslated region (3′-UTR) of c-MYC, inhibiting its translation and leading to decreased c-MYC protein levels. Moreover, the expression of this miRNA was sufficient to decrease the proliferation rate of t(4;14) MM cells. Chromatin immunoprecipitation analysis showed that MMSET binds to the miR-126* promoter along with the KAP1 corepressor and histone deacetylases, and is associated with heterochromatic modifications, characterized by increased trimethylation of H3K9 and decreased H3 acetylation, leading to miR-126* repression. Collectively, this study shows a novel mechanism that leads to increased c-MYC levels and enhanced proliferation of t(4;14) MM, and potentially other cancers with high MMSET expression.

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Acknowledgements

We thank Dr Louis Staudt for providing the MMSET-shRNA cells and Dr Marcus Peter for helpful suggestions. This work was supported by NIH Grant CA123204, a Leukemia and Lymphoma Specialized Center of Research grant, a NIH Physical Science Oncology Center Grant U54CA143869 and Epizyme, Inc. (to JDL). EM-G was supported by a European Hematology Association Fellowship, RP by NRSA HL099177 and TE by an Alfonso Martin Escudero fellowship.

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  1. D-J Min and T Ezponda: These two authors contributed equally to this work.

Authors and Affiliations

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

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

  2. Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    M K Kim

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    V Basrur & K S Elenitoba-Johnson

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  1. D-J Min
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Min, DJ., Ezponda, T., Kim, M. et al. MMSET stimulates myeloma cell growth through microRNA-mediated modulation of c-MYC. Leukemia 27, 686–694 (2013). https://doi.org/10.1038/leu.2012.269

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