miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator

Simon Husby, Ulrik Methner Ralfkiær, Christian Garde, Roza Zandi, Sara Ek, Arne Kolstad, Mats Jerkeman, Anna Laurell, Riikka Räty, Lone B. Pedersen, Anja Pedersen, Mats Ehinger, Christer Sundström, Marja-Liisa Karjalainen-Lindsberg, Jan Delabie, Erik Clasen-Linde, Peter Brown, Jack B. Cowland, Christopher Workman, Christian H. GeislerKirsten Grønbæk

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    Abstract

    Recent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.
    Original languageEnglish
    JournalBlood
    Volume125
    Issue number17
    Pages (from-to)2669-2677
    Number of pages10
    ISSN0006-4971
    DOIs
    Publication statusPublished - 2015

    Cite this

    Husby, S., Ralfkiær, U. M., Garde, C., Zandi, R., Ek, S., Kolstad, A., Jerkeman, M., Laurell, A., Räty, R., Pedersen, L. B., Pedersen, A., Ehinger, M., Sundström, C., Karjalainen-Lindsberg, M-L., Delabie, J., Clasen-Linde, E., Brown, P., Cowland, J. B., Workman, C., ... Grønbæk, K. (2015). miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator. Blood, 125(17), 2669-2677. https://doi.org/10.1182/blood-2014-06-584193