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Lymphoma

Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity

Leukemia volume 27, pages 2341–2350 (2013)Cite this article

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Abstract

c-MYC (hereafter MYC) overexpression has been recognized in aggressive B-cell lymphomas and linked to adverse prognosis. MYC activation results in widespread repression of micro-RNA (miRNA) expression and associated with lymphoma aggressive progression. Our recent study identified a MYC-miRNA-EZH2 feed-forward loop linking overexpression of MYC, EZH2 and miRNA repression. Here, using a novel small-molecule BET bromodomain inhibitor, JQ1, and the EZH2 inhibitor, DZNep, we demonstrated that combined treatment of JQ1 and DZNep cooperatively disrupted MYC activation, resulting in a greater restoration of miR-26a expression and synergistically suppressed lymphoma growth and clonogenicity in aggressive lymphoma cells. Furthermore, CHIP assay demonstrated that MYC recruited EZH2 to miR-26a promoter and cooperatively repressed miR-26a expression in aggressive lymphoma cell lines, as well as primary lymphoma cells. Loss- or gain-of-function approaches revealed that miR-26a functioned as a tumor suppressor miRNA and mediated the combinatorial effects of JQ1 and DZNep. These findings represent a novel promising approach for silencing MYC-miRNA-EZH2 amplification loop for combinatorial therapy of aggressive B-cell lymphomas.

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Acknowledgements

This work was supported by grants from the National Cancer Institutes (R01 CA137123, to JT), Maher Fund (to JT) and Lymphoma Research Foundation (to JT), and supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to VM). JQ1 was kindly provided by James E Bradner (Boston, MA, USA), and DZNep was kindly provided by Victor E Marquez (Frederick, MD, USA).

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Authors and Affiliations

  1. Department of Malignant Hematology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    X Zhao, T Lwin, X Zhang, A Huang, J Wang, W S Dalton, E Sotomayor & J Tao

  2. Department of Immunology and Surgery, Tianjin Cancer Hospital, Tianjin, China

    X Zhang & J Wang

  3. Chemical Biology Laboratory, Frederick National Laboratory for Cancer Research, CCR, National Cancer Institute, NIH, Frederick, MD, USA

    V E Marquez

  4. Department of Pathology, Weill-Cornell Medical College, New York, NY, USA

    S Chen-Kiang

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  1. X Zhao
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Correspondence to J Tao.

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Zhao, X., Lwin, T., Zhang, X. et al. Disruption of the MYC-miRNA-EZH2 loop to suppress aggressive B-cell lymphoma survival and clonogenicity. Leukemia 27, 2341–2350 (2013). https://doi.org/10.1038/leu.2013.94

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