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Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma

Oncogene volume 33, pages 2191–2203 (2014)Cite this article

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Abstract

The proto-oncogene BMI1 and its product, Bmi1, is overexpressed in various types of tumors, particularly in aggressive tumors and tumors resistant to conventional chemotherapy. BMI1/Bmi1 is also crucially involved in cancer-initiating cell maintenance, and is recurrently upregulated in mantle cell lymphoma (MCL), especially aggressive variants. Recently, side population (SP) cells were shown to exhibit tumor-initiating characteristics in various types of tumors. In this study, we show that recurrent MCL cases significantly exhibit upregulation of BMI1/Bmi1. We further demonstrate that clonogenic MCL SP shows such tumor-initiating characteristics as high tumorigenicity and self-renewal capability, and that BMI1 was upregulated in the SP from recurrent MCL cases and MCL cell lines. On screening for upstream regulators of BMI1, we found that expression of microRNA-16 (miR-16) was downregulated in MCL SP cells by regulating Bmi1 in the SPs, leading to reductions in tumor size following lymphoma xenografts. Moreover, to investigate downstream targets of BMI1 in MCL, we performed cross-linking/chromatin immunoprecipitation assay against MCL cell lines and demonstrated that Bmi1 directly regulated pro-apoptotic genes such as BCL2L11/Bim and PMAIP1/Noxa, leading to enhance anti-apoptotic potential of MCL. Finally, we found that a proteasome inhibitor bortezomib, which has been recently used for relapsed MCL, effectively induced apoptosis among MCL cells while reducing expression of Bmi1 and increasing miR-16 in MCL SP. These results suggest that upregulation of BMI1 and downregulation of miR-16 in MCL SP has a key role in the disease’s progression by reducing MCL cell apoptosis. Our results provide important new insight into the pathogenesis of MCL and strongly suggest that targeting BMI1/Bmi1 might be an effective approach to treating MCL, particularly refractory and recurrent cases.

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Acknowledgements

This work is supported by a Grant-in-Aid from the Japan Society for the Promotion of Science (HT). We wish to express our appreciation to Ms E Kobayashi, Y Abe, K Iwamoto, H Kataho and Mr J Yamashita for their outstanding technical assistance, Drs T Nanjo (Akita University, Akita, Japan), S Nakamura (Nagoya University, Nagoya, Japan) and R Ichinohasama (Tohoku University, Sendai, Japan) for their histological and/or clinical diagnosis of MCL. Drs N Takahashi (Akita University), N Takahashi (Akita University), Y Michishita (Akita University), K Honda (Akita University), M Kume (Hiraka General Hospital), H Oyagi (Hiraka General Hospital), M Katayama (Aichi Cancer Center) and F Arakawa (Kurume University) for collection of primary lymphoma samples and constructive discussion.

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  1. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    K Teshima, M Nara, A Watanabe, M Ito, S Ikeda, K Sawada & H Tagawa

  2. Department of Internal Medicine, Yamamoto Kumiai General Hospital, Noshiro, Japan

    Y Hatano

  3. Department of Pathology, Kurume University School of Medicine, Kurume, Japan

    K Oshima

  4. Department of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan

    M Seto

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  1. K Teshima
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Teshima, K., Nara, M., Watanabe, A. et al. Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma. Oncogene 33, 2191–2203 (2014). https://doi.org/10.1038/onc.2013.177

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