title: Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes.
abstract: 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.
authors.affiliation: Center for Applied Medical Research (CIMA), Division of Oncology, University of Navarra, Avda Pio XII, 55, Pamplona 31008, Spain.
authors.forename: Fanny
authors.initials: F
authors.lastname: Rubio-Moscardo
authors.forename: David
authors.initials: D
authors.lastname: Blesa
authors.forename: Cinta
authors.initials: C
authors.lastname: Mestre
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.forename: Theo
authors.initials: T
authors.lastname: Balasas
authors.forename: Adalberto
authors.initials: A
authors.lastname: Benito
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Joan
authors.initials: J
authors.lastname: Climent
authors.forename: Jose I
authors.initials: JI
authors.lastname: Martinez
authors.forename: Markus
authors.initials: M
authors.lastname: Schilhabel
authors.forename: E Lorraine
authors.initials: EL
authors.lastname: Karran
authors.forename: Stefan
authors.initials: S
authors.lastname: Gesk
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Ronald
authors.initials: R
authors.lastname: deLeeuw
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Fernandez-Luna
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinkel
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins