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

Rubio-Moscardó, Fanny

doi:10.1182/blood-2005-05-2013

Cited by 122 publications

(95 citation statements)

References 52 publications

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“…We also demonstrate that sensitivity to TRAIL in MCL cells is not linked to TRAIL receptor expression. TRAIL-induced apoptosis has recently been described as dependent on TRAIL-RI and/or TRAIL-R2 dosage in B cell lymphomas, and associated with the 8p21.3 deletion, frequently observed in the leukemic form of MCL (16). Our results show that 8p genomic loss is associated neither with response to TRAIL, with mRNA levels, nor with the membrane expression of the TRAIL receptors.…”

Section: Discussionmentioning

confidence: 41%

“…Genetic characterization of these cell lines has been published recently (15). JVM-2 and Rec-1 cells have been previously shown to harbor a genomic loss at 8p21 (16), presumably affecting the TRAIL receptor locus. MCL cell lines (0.3-0.5 ϫ 10 6 cells/ml) were cultured in RPMI 1640 culture medium (Invitrogen Life Technologies), supplemented with 10% heat-inactivated FCS (Invitrogen Life Technologies), 2 mM glutamine, 50 g/ml penicillin-streptomycin, and 100 g/ml of the antimycoplasm agent normocin (Amaxa).…”

Section: Cell Linesmentioning

confidence: 99%

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Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level

Roué

Pérez-Galán

López‐Guerra

et al. 2007

The Journal of Immunology

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In an attempt to circumvent the intrinsic resistance of mantle cell lymphoma (MCL) cells to apoptosis, we have analyzed their sensitivity to the extrinsic apoptotic signal triggered by TRAIL. We show here that TRAIL can trigger apoptosis in a majority of MCL cell lines and primary cultures, irrespective of receptor levels, Bcl-2 family members, or caspase regulator expression. MCL sensitivity to TRAIL was closely linked to the activity of the NF-κB p50 factor and to the consequent expression of cellular FLIP (c-FLIP), which accumulated into the TRAIL-dependent complex in resistant cells. c-FLIP transient knockdown overcame MCL resistance to TRAIL, while NF-κB inhibitors differentially modulated TRAIL cytotoxicity. Indeed, bortezomib increased TRAIL cytotoxic effects in sensitive cells, but led to the intracellular accumulation of c-FLIP, impeding full synergistic interaction. In contrast, the IκB kinase inhibitor BMS-345541 led to decreased c-FLIP expression and allowed all MCL samples to undergo TRAIL-mediated apoptosis. These results present the combination of TRAIL stimulation and IκB kinase inhibition as a new approach to MCL therapy.

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Section: Discussionmentioning

confidence: 41%

Section: Cell Linesmentioning

confidence: 99%

Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level

Roué

Pérez-Galán

López‐Guerra

et al. 2007

The Journal of Immunology

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“…Losses of 8p include loss of TNFRSF10A/B (TRAIL-R1/2) tumour suppressor genes, whose inactivation in B-cell neoplasm is related with non-function of apoptosis and aggressive transformation (Rubio-Moscardo et al, 2005). Therefore, we could have expected a more aggressive disease in our cases but this did not occur in Patient 4, who remains alive with stable disease at 3 years after diagnosis.…”

Section: Discussionmentioning

confidence: 70%

A new genetic abnormality leading to TP53 gene deletion in chronic lymphocytic leukaemia

López¹,

Baumann²,

Costa³

et al. 2011

Br J Haematol

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SummaryThe analysis of chromosomal abnormalities provides significant prognostic information in patients with chronic lymphocytic leukaemia (CLL), a disease with a highly heterogeneous clinical course. Chromosomal abnormalities commonly found are trisomy 12, del(13)(q14), del(11)(q22‐23), del(17)(p13) and del(6)(q21). Translocations are present in some patients and affect regions recurrently involved in CLL. This report describes the clinical and pathological characteristics of four CLL patients showing a new recurrent chromosomal abnormality dic(8;17)(p11;p11), that implied loss of the TP53 gene in all cases. In addition, TP53 gene was mutated in three out of four patients. Mechanically, Low Copy Repeats (LCR) in 17p12 and 8p11 may explain the origin of the translocation by non‐allelic homologous recombination (NAHR). Isolated dic(8;17)(p11;p11) in patients with mutated IGHV genes status may not have the same prognostic impact as other mutations or deletions affecting the TP53 gene. Larger series are needed to better evaluate the clinical impact of this chromosomal aberration during the course of the disease.

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“…Data using 45 human B cell non-Hodgkin lymphoma cell lines suggest that monoallelic deletion of 650-kb region on chromosome 8p21.3, including TRAIL-R1 and TRAIL-R2, is a frequent event (36). No altered promoter methylation on the remaining alleles was found, whereas downregulation of DR4 and DR5 mRNA was found with concomitant loss of cell surface expression of TRAIL receptor proteins and resistance to apoptosis induced by FLAG-tagged TRAIL in vitro that was correlated with monoallelic deletion.…”

Section: Wt 119 Days) Trail-r-deficient Lymphomas Harbored Apoptoticmentioning

confidence: 99%

TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis

Finnberg¹,

Klein‐Szanto²,

El‐Deiry³

2008

J. Clin. Invest.

155

129

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Preclinical data support the potential of the death-signaling receptors for TRAIL as targets for cancer therapy. However, it is unclear whether these death-signaling receptors suppress the emergence and growth of malignant tumors in vivo. Herein we show that TNF-related apoptosis-inducing ligand receptor (TRAIL-R), the only proapoptotic death-signaling receptor for TRAIL in the mouse, suppresses inflammation and tumorigenesis. Loss of a single TRAIL-R allele on the lymphoma-prone Eμ-myc genetic background significantly reduced median lymphoma-free survival. TRAIL-R-deficient lymphomas developed with equal frequency irrespective of mono-or biallelic loss of TRAIL-R, had increased metastatic potential, and showed apoptotic defects relative to WT littermates. In addition, TRAIL-R -/-mice showed decreased long-term survival following a sublethal dose of ionizing radiation. Histological evaluation of moribund irradiated TRAIL-R -/-animals showed hallmarks of bronchopneumonia as well as tumor formation with increased NF-κB p65 expression. TRAIL-R also suppressed diethylnitrosamine-induced (DEN-induced) hepatocarcinogenesis, as an increased number of large tumors with apoptotic defects developed in the livers of DEN-treated TRAIL-R -/-mice. Thus TRAIL-R may function as an inflammation and tumor suppressor in multiple tissues in vivo.

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

Cited by 122 publications

References 52 publications

Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level

Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level

A new genetic abnormality leading to TP53 gene deletion in chronic lymphocytic leukaemia

TRAIL-R deficiency in mice promotes susceptibility to chronic inflammation and tumorigenesis

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