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.