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Lymphoma

The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

Leukemia volume 26, pages 1064–1072 (2012)Cite this article

Abstract

The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17∼92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P=0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17∼92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17∼92 cluster. Overexpression of miR-17∼92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17∼92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17∼92 cluster may therefore provide a novel therapeutic approach for patients with MCL.

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Acknowledgements

This work was supported in part by the National Institutes of Health grant U01 CA114778 to WCC; the Lymphoma Research Foundation/Millennium Pharmaceuticals, Inc. Clinical Investigator Career Development Award to KF; and UNMC Eppley Cancer Center Pilot Grant to KF; MJ and XH are supported by a scholarship from the China Scholarship Council.

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Author notes

  1. E Rao and C Jiang: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Pathology and Microbiology and Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    E Rao, C Jiang, M Ji, X Huang, J Iqbal, T W McKeithan, W C Chan & K Fu

  2. Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Beijing, China

    E Rao & Y Zhao

  3. Graduate School, Chinese Academy of Sciences, Beijing, China

    E Rao

  4. Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    G Lenz

  5. Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Health Institutes, Bethesda, MD, USA

    G Lenz & L M Staudt

  6. Division of Cancer Treatment and Diagnosis, Biometrics Research Branch, National Cancer Institute, National Health Institutes, Bethesda, MD, USA,

    G Wright

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Correspondence to K Fu.

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Author Contributions

TWM, WCC and KF designed the study and provided administrative support; WCC and KF provided the study materials and patient information; ER, CJ, MJ, JI, XH, GL, GW and KF collected and assembled the data; ER, CJ, JI, GL, GW, LS, YZ, TWM, WCC and KF performed data analysis and interpretation; ER, CJ, TWM and KF wrote the manuscript; all authors have checked and approved the final version of the paper.

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Rao, E., Jiang, C., Ji, M. et al. The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia 26, 1064–1072 (2012). https://doi.org/10.1038/leu.2011.305

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