Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes

Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma (B-NHL), suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, fluorescence in situ hybridization (FISH) mapping, DNA sequencing...

Full description

Saved in:

Bibliographic Details
Published in:	Blood Vol. 106; no. 9; pp. 3214 - 3222
Main Authors:	Rubio-Moscardo, Fanny, Blesa, David, Mestre, Cinta, Siebert, Reiner, Balasas, Theo, Benito, Adalberto, Rosenwald, Andreas, Climent, Joan, Martinez, Jose I., Schilhabel, Markus, Karran, E. Lorraine, Gesk, Stefan, Esteller, Manel, deLeeuw, Ronald, Staudt, Louis M., Fernandez-Luna, Jose Luis, Pinkel, Daniel, Dyer, Martin J.S., Martinez-Climent, Jose A.
Format:	Journal Article
Language:	English
Published:	Washington, DC Elsevier Inc 01-11-2005 The Americain Society of Hematology
Subjects:	Apoptosis Apoptosis Regulatory Proteins - metabolism Biological and medical sciences Cell Line, Tumor Chromosome Deletion Chromosomes, Human, Pair 8 - genetics Down-Regulation Gene Expression Profiling Genes, Tumor Suppressor - physiology Hematologic and hematopoietic diseases Humans Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphoma, B-Cell - genetics Medical sciences Membrane Glycoproteins - metabolism Mutation - genetics Receptors, TNF-Related Apoptosis-Inducing Ligand Receptors, Tumor Necrosis Factor - genetics Receptors, Tumor Necrosis Factor - metabolism TNF-Related Apoptosis-Inducing Ligand Tumor Necrosis Factor-alpha - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Human Pathogenesis TNF-Related Apoptosis-Inducing Ligand Receptor 1 TNF-Related Apoptosis-Inducing Ligand Receptor 2 Malignant hemopathy B-Lymphocyte Chromosome C8 Lymphoma Lymphoproliferative syndrome Deletion Genetics TNF related apoptosis inducing ligand Candidate gene Apoptosis Tumor suppressor gene Biological receptor
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma (B-NHL), suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, fluorescence in situ hybridization (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 bacterial artificial chromosome (BAC) clones 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 quantitative reverse transcriptase–polymerase chain reaction (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.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2005-05-2013