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

TY - JOUR

T1 - miR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator

AU - Husby, Simon

AU - Ralfkiaer, Ulrik

AU - Garde, Christian

AU - Zandi, Roza

AU - Ek, Sara

AU - Kolstad, Arne

AU - Jerkeman, Mats

AU - Laurell, Anna

AU - Räty, Riikka

AU - Pedersen, Lone B

AU - Pedersen, Anja

AU - Ehinger, Mats

AU - Sundström, Christer

AU - Karjalainen-Lindsberg, Marja-Liisa

AU - Delabie, Jan

AU - Clasen-Linde, Erik

AU - Brown, Peter de Nully

AU - Cowland, Jack B

AU - Workman, Christopher T

AU - Geisler, Christian H

AU - Grønbæk, Kirsten

N1 - © 2015 by The American Society of Hematology.

PY - 2015/4/23

Y1 - 2015/4/23

N2 - 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.

AB - 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.

KW - Aged

KW - Apoptosis

KW - Biomarkers, Tumor

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Disease-Free Survival

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lymphoma, Mantle-Cell

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - Prognosis

KW - Prospective Studies

KW - Transfection

KW - Up-Regulation

U2 - 10.1182/blood-2014-06-584193

DO - 10.1182/blood-2014-06-584193

M3 - Journal article

C2 - 25736311

SN - 0006-4971

VL - 125

SP - 2669

EP - 2677

JO - Blood

JF - Blood

IS - 17

ER -