Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes
Open accessAbstract
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 TR…
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CLL cells with del(8p) have been found to be refractory to TRAIL-induced apoptosis.
“CLL cells with del(8p) have been found to be refractory to TRAIL-induced apoptosis(47).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [47]
Del(8p) results in haploinsufficiency of tumor necrosis factor-related apoptosis-inducing ligand-R (TRAIL-R) protein, which binds to TRAIL and induces apoptosis, suggesting function as a tumor suppressor.
“Del(8p) results in haploinsufficiency of tumor necrosis factor-related apoptosis-inducing ligand-R (TRAIL-R) protein, which binds to TRAIL and induces apoptosis, suggesting function as a tumor suppressor (47).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [47]
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Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo.
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Apoptosis: A Review of Programmed Cell Death
Elmore, S. (2007) · Toxicologic Pathology · doi:10.1080/01926230701320337 · Cited by 13,853 · see citing works
Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy
Gruessner, C., Wiestner, A., & Sun, C. (2025) · Leukemia & Lymphoma · doi:10.1080/10428194.2025.2466101 · Cited by 6 · see citing works
“…apoptosis, suggesting function as a tumor suppressor [46]. cll cells with del(8p) have been found to be refractory to tRAil-induced apoptosis [46]. in one longitudinal genomic study of 5 cll patients who had disease progression on ibrutinib, del(8p) was observed in 3 patients with BTK and…”
- Authors
- Rubio-Moscardo, F.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2005-11-01
- Volume
- 106
- Issue
- 9
- Pages
- 3214-3222
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2149455148
- Cited by
- 157
- References
- 3
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 7 · 2022: 3 · 2021: 8 · 2020: 13 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 8 · 2015: 9 · 2014: 10 · 2013: 11 · 2012: 9
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Deposito Adademico Digital Universidad De Navarra (University of Navarra) (submittedVersion, other-oa)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- B-cell non-Hodgkin lymphoma, TRAIL receptor 1, TRAIL receptor 2, tumor suppressor, monoallelic deletion, TRAIL-induced apoptosis, apoptosis resistance, mantle cell lymphoma, epigenetic silencing, promoter methylation
- MeSH terms
- Chromosome Deletion, Chromosomes, Human, Pair 8, Humans, Membrane Glycoproteins, Mutation, Tumor Necrosis Factor-alpha, Down-Regulation, Genes, Tumor Suppressor, Lymphoma, B-Cell, Apoptosis, Receptors, Tumor Necrosis Factor, Gene Expression Profiling, Tumor Suppressor Proteins, Cell Line, Tumor, Apoptosis Regulatory Proteins, Receptors, TNF-Related Apoptosis-Inducing Ligand, TNF-Related Apoptosis-Inducing Ligand
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