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MicroRNA Expression, Chromosomal Alterations, and Immunoglobulin Variable Heavy Chain Hypermutations in Mantle Cell Lymphomas

Departments of ¹ Pathology (Hematopathology Unit) and ² Hematology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; ³ Department of Statistics, Technical University of Catalonia; ⁴ Department of Pathology, Hospital del Mar, Barcelona, Spain; ⁵ Institute of Pathology, University of Würzburg, Würzburg, Germany; and ⁶ Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Stuttgart, Germany

Requests for reprints: Luis Hernández, Lab 302, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, C/Casanova 135, 08036 Barcelona, Spain. Phone: 34-932275400, ext. 2129; Fax: 34-932275717; E-mail: hernan{at}clinic.ub.es.

Key Words: microRNA • mantle cell lymphoma • genomic imbalances • miR-17-92 • MYC

The contribution of microRNAs (miR) to the pathogenesis of mantle cell lymphoma (MCL) is not well known. We investigated the expression of 86 mature miRs mapped to frequently altered genomic regions in MCL in CD5⁺/CD5^– normal B cells, reactive lymph nodes, and purified tumor cells of 17 leukemic MCL, 12 nodal MCL, and 8 MCL cell lines. Genomic alterations of the tumors were studied by single nucleotide polymorphism arrays and comparative genomic hybridization. Leukemic and nodal tumors showed a high number of differentially expressed miRs compared with purified normal B cells, but only some of them were commonly deregulated in both tumor types. An unsupervised analysis of miR expression profile in purified leukemic MCL cells revealed two clusters of tumors characterized by different mutational status of the immunoglobulin genes, proliferation signature, and number of genomic alterations. The expression of most miRs was not related to copy number changes in their respective chromosomal loci. Only the levels of miRs included in the miR-17-92 cluster were significantly related to genetic alterations at 13q31. Moreover, overexpression of miR-17-5p/miR-20a from this cluster was associated with high MYC mRNA levels in tumors with a more aggressive behavior. In conclusion, the miR expression pattern of MCL is deregulated in comparison with normal lymphoid cells and distinguishes two subgroups of tumors with different biological features. [Cancer Res 2009;69(17):7071–8]