Genome-wide miRNAprofiling of mantle cell lymphoma reveals a distinct subgroup with poor prognosis

Authors

Javeed Iqbal, University of Nebraska Medical Center
Yulei Shen, University of Nebraska Medical Center
Yanyan Liu, University of Nebraska Medical Center
Kai Fu, University of Nebraska Medical Center
Elaine S. Jaffe, National Institutes of HealthFollow
Cuiling Liu, University of Nebraska Medical Center
Zhongfeng Liu, University of Nebraska Medical Center
Cynthia M. Lachel, University of Nebraska Medical Center
Karen Deffenbacher, University of Nebraska Medical Center
Timothy C. Greiner, University of Nebraska Medical Center
Julie M. Vose, University of Nebraska Medical Center
Sharathkumar Bhagavathi, University of Nebraska Medical Center
Louis M. Staudt, Center for Cancer Research
Lisa Rimsza, University of Arizona
Andreas Rosenwald, University of Wu¨rzburg
German Ott, Robert Bosch Hospital
Jan Delabie, University of Oslo
Elias Campo, University of Barcelona
Rita M. Braziel, Oregon Health and Science University
James R. Cook, Cleveland Clinic
Raymond R. Tubbs, Cleveland Clinic
Randy D. Gascoyne, British Columbia Cancer Agency
James O. Armitage, University of Nebraska Medical Center
Dennis D. Weisenburger, University of Nebraska Medical Center
Timothy W. McKeithan, University of Nebraska Medical Center
Wing C. Chan, University of Nebraska Medical Center

Date of this Version

5-2012

Citation

BLOOD, 24 May 2012 Volume 119, Number 21; doi 10.1182/blood-2011-07-370122

Abstract

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n =7) and compared them with small lymphocytic leukemia/ lymphoma (n =12), aggressive B-cell lymphomas (n =138), normal B-cell subsets, and stromal cells.We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNAclassifier showed consistent results in formalinfixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.