Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis

Xerri, Luc; Devilard, Élisabeth; Hassoun, Jacques; Haddad, Patrick; Birg, Françoise

doi:10.1038/sj.leu.2400815

Cited by 50 publications

(45 citation statements)

References 9 publications

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“…In order to assess the value of TRAIL, we have determined its toxicity to primary B-CLL cells from patients as opposed to the use of cell lines, which have been used in most other studies. B-CLL cells were resistant to TRAIL and CD95 (Table 1) in accord with other studies (Xerri et al, 1997(Xerri et al, , 1998Wang et al, 1997;Plumas et al, 1998). Thus, in vitro resistance to TRAIL may be common to many primary haematological malignancies (Snell et al, 1997).…”

Section: Discussionsupporting

confidence: 76%

“…In contrast, TRAIL may represent a more suitable ligand for exploitation, as it does not generally induce cell death in normal tissues. B-CLL and other B cell malignancies, such as B-cell non-Hodgkin's lymphoma (B-NHL), are commonly resistant to CD95-mediated apoptosis (Wang et al, 1997;Xerri et al, 1997;Plumas et al, 1998). The mechanism(s) of CD95 resistance in these cells is unclear, but may include lack of expression of functional receptors or overexpression of inhibitory molecules.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

et al. 2002

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Primary B cells from B cell chronic lymphocytic leukaemia (B-CLL) were resistant to the novel selective cytotoxic agent, TNF-related apoptosis-inducing ligand (TRAIL). Low levels of the death-inducing TRAIL receptors, TRAIL-R1 and TRAIL-R2 but not the putative 'decoy' receptors, TRAIL-R3 and TRAIL-R4, were expressed on the surface of B-CLL cells. Resistance to TRAIL was upstream of caspase-8 activation, as little or no caspase-8 was processed in TRAIL-treated B-CLL cells. Low levels of a TRAIL death-inducing signalling complex (DISC) were formed in these cells, accompanied by the recruitment of endogenous FADD, caspase-8 and c-FLIP L but not c-FLIP S . Both caspase-8 and c-FLIP L were cleaved to form two stable intermediates of *43 kDa, which remained associated with the DISC. Caspase-8 was not further processed to its active heterotetramer. Thus the resistance of B-CLL cells to TRAIL may be due partly to low surface expression of the death receptors resulting in low levels of DISC formation and also to the high ratio of c-FLIP L to caspase-8 within the DISC, which would prevent further activation of caspase-8. Our results highlight the possibility of sensitising B-CLL cells to TRAIL by modulation of c-FLIP levels or by upregulation of surface expression of death receptors.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

et al. 2002

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“…Malignant cells, both lymphoid and non-lymphoid, manifest resistance to Fasmediated apoptosis [140][141][142][143][144][145][146][147][148][149]. Inasmuch as inhibition of Fas signaling for cell death is associated with tumor development and progression, it appears that Fas-mediated apoptosis constitutes at least a portion of anti-tumor immunity, and that some malignancies take advantage of mechanisms that block Fas killing to maintain viability and co-exist within the framework of a normal immune system [100,101], [150][151][152][153].…”

Section: Summary and Discussionmentioning

confidence: 99%

Inducible resistance to Fas-mediated apoptosis in B cells

Rothstein

2000

Cell Res

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Apoptosis produced in B cells through Fas (APO-1, CD95) triggering is regulated by signals derived from other surface receptors: CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas-induced cell death, whereas antigen receptor engagement, or IL-4R engagement, inhibits Fas killing and in so doing induces a state of Fas-resistance, even in otherwise sensitive, CD40-stimulated targets. Surface immunoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas-resistance that differentially depend on PKC and STAT6, respectively. Further, surface immunoglobulin signaling for inducible Fas-resistance bypasses Btk, requires NF-κB, and entails new macromolecular synthesis. Terminal effectors of B cell Fas-resistance include the known anti-apoptotic gene products, Bcl-xL and FLIP, and a novel anti-apoptotic gene that encodes FAIM (Fas Apoptosis Inhibitory Molecule). faim was identified by differential display and exists in two alter-

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“…35 FasL expression is also increased in malignant lymphomas, Hodgkin's disease and large granular lymphocyte leukemia. 46,47 Whether the increased expression of FasL contributes to the survival and growth of leukemic or dysplastic clones is unknown.…”

Section: Discussionmentioning

confidence: 99%

Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival

et al. 1999

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Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis

Abstract: populations.

Cited by 50 publications

References 9 publications

Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

Mechanisms of resistance to TRAIL-induced apoptosis in primary B cell chronic lymphocytic leukaemia

Inducible resistance to Fas-mediated apoptosis in B cells

Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival

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