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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3214-3222. Prepublished online as a Blood First Edition Paper on July 28, 2005; DOI 10.1182/blood-2005-05-2013. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: 2005-05-2013v1 106/9/3214    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rubio-Moscardo, F. Articles by Martinez-Climent, J. A Search for Related Content PubMed PubMed Citation Articles by Rubio-Moscardo, F. Articles by Martinez-Climent, J. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 19, 2005 Accepted July 5, 2005 Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes Fanny Rubio-Moscardo, David Blesa, Cinta Mestre, Reiner Siebert, Theo Balasas, Adalberto Benito, Andreas Rosenwald, Joan Climent, Jose I Martinez, Markus Schilhabel, E L Karran, Stefan Gesk, Manel Esteller, Ronald deLeeuw, Louis M Staudt, Jose L Fernandez-Luna, Daniel Pinkel, Martin J Dyer, and Jose A Martinez-Climent* Center for Applied Medical Research (CIMA), Division of Oncology, University of Navarra, Pamplona, Spain; Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Valencia, Spain Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Valencia, Spain Institute of Human Genetics, University Hospital Schleswig -Holstein, Kiel, Germany MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom Molecular Genetics Unit, Hospital Universitario Universidad Marques de Valdecilla, Santander, Spain Department of Pathology, University of Wurzburg, Germany Instituto Investigaciones Citologicas, Valencia, Spain Institute for Molecular Biotechnology, Jena, Germany Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain British Columbia Cancer Agency, Vancouver, Canada National Cancer Institute, Bethesda, MD, USA Cancer Research Institute, University of California, San Francisco, CA, USA * Corresponding author; email: jamcliment{at}unav.es. Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma, suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, FISH mapping, DNA sequencing and functional studies. A minimal deleted region (MDR) of 600 kb. was defined in chromosome 8p21.3, with one mantle cell lymphoma cell line (Z138) exhibiting monoallelic deletion of 650 kb. The MDR extended from BACs RP11-382J24 and RP11-109B10 and included the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene loci. Sequence analysis of the individual expressed genes within the MDR and DNA sequencing of the entire MDR in Z138 did not reveal any mutation. Gene expression analysis and QRT-PCR showed down-regulation of TRAIL-R1 and TRAIL-R2 receptor genes as a consistent event in B-NHL with 8p21.3 loss. Epigenetic inactivation was excluded via promoter methylation analysis. In vitro studies showed that TRAIL-induced apoptosis was dependent on TRAIL-R1 and/or R2 dosage in most tumors. Resistance to apoptosis of cell lines with 8p21.3 deletion was reversed by restoration of TRAIL-R1 or TRAIL-R2 expression by gene transfection. Our data suggest that TRAIL-R1 and TRAIL-R2 act as dosage-dependent tumor suppressor genes whose monoallelic deletion can impair TRAIL-induced apoptosis in B-cell lymphoma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Hartmann, V. Fernandez, V. Moreno, J. Valls, L. Hernandez, F. Bosch, P. Abrisqueta, W. Klapper, M. Dreyling, E. Hoster, et al. Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue J. Clin. Oncol., October 20, 2008; 26(30): 4966 - 4972. [Abstract] [Full Text] [PDF] A. Ramalingam, J. B. Duhadaway, E. Sutanto-Ward, Y. Wang, J. Dinchuk, M. Huang, P. S. Donover, J. 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