Original Article

Leukemia (2010) 24, 1335–1342; doi:10.1038/leu.2010.91; published online 20 May 2010

Lymphoma

Mantle cell lymphoma: transcriptional regulation by microRNAs

L Di Lisio1, G Gómez-López2, M Sánchez-Beato1, C Gómez-Abad1, M E Rodríguez1, R Villuendas1, B I Ferreira3, A Carro2, D Rico2, M Mollejo4, M A Martínez5, J Menárguez6, A Díaz-Alderete7, J Gil7, J C Cigudosa3, D G Pisano2, M A Piris1 and N Martínez1

  1. 1Lymphoma Group, Molecular Pathology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  2. 2Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  3. 3Molecular Cytogenetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
  4. 4Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain
  5. 5Department of Pathology, Hospital Doce de Octubre, Madrid, Spain
  6. 6Department of Pathology, Hospital Gregorio Marañon, Madrid, Spain
  7. 7Department of Immunology, Hospital Gregorio Marañon, Madrid, Spain

Correspondence: Dr MA Piris, Lymphoma Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas, C/ Melchor Fernández Almagro no. 3, Madrid E-28029, Spain. E-mail: mapiris@cnio.es

Received 1 December 2009; Revised 19 February 2010; Accepted 30 March 2010; Published online 20 May 2010.

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Abstract

Mantle cell lymphoma (MCL) pathogenesis is still partially unexplained. We investigate the importance of microRNA (miRNA) expression as an additional feature that influences MCL pathway deregulation and may be useful for predicting patient outcome. Twenty-three MCL samples, eight cell lines and appropriate controls were screened for their miRNAs and gene expression profiles and DNA copy-number changes. MCL patients exhibit a characteristic signature that includes 117 miRNA (false discovery rate <0.05). Combined analysis of miRNAs and the gene expression profile, paired with bioinformatics target prediction (miRBase and TargetScan), revealed a series of genes and pathways potentially targeted by a small number of miRNAs, including essential pathways for lymphoma survival such as CD40, mitogen-activated protein kinase and NF-κB. Functional validation in MCL cell lines demonstrated NF-κB subunit nuclear translocation to be regulated by the expression of miR-26a. The expression of 12 selected miRNAs was studied by quantitative PCR in an additional series of 54 MCL cases. Univariate analysis identified a single miRNA, miR-20b, whose lack of expression distinguished cases with a survival probability of 56% at 60 months. In summary, using a novel bioinformatics approach, this study identified miRNA changes that contribute to MCL pathogenesis and markers of potential utility in MCL diagnosis and clinical prognostication.

Keywords:

MCL; miRNA; integrative genomic analysis