Predominant expression of the long isoform of Bcl‐x (Bcl‐xL) in human lymphomas

Xerri, Luc; Parc, Patricia; Brousset, Pierre; Schlaifer, Daniel; Hassoun, Jacques; Reed, John C.; Krajewski, Stanislas; Birnbaum, Daniel

doi:10.1046/j.1365-2141.1996.423958.x

Cited by 90 publications

(64 citation statements)

References 15 publications

(38 reference statements)

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“…We analysed Bcl-2 expression using reverse transcriptase-polymerase chain reaction (RT-PCR) in the 18 NHL cases, and found no correlation between the level of expression and the sensitivity to Fas killing (data not shown). These results do not exclude a possible role of other members of the Bcl-2 family, such as Bcl-xL, which was demonstrated to decrease Fas killing when transfected into apoptosis-sensitive myeloma cells (Gauthier et al, 1996); we reported previously that the majority of human NHLs express substantial amounts of Bcl-xL (Xerri et al, 1996). The defect could be linked alternatively to the effectors of apoptosis including caspases, which are known to control the distal point of a common apoptotic pathway shared by many cell death inductors (Casciola-Rosen et al, 1996;Henkart, 1996).…”

Section: Discussioncontrasting

confidence: 58%

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

Xerri

Bouabdallah²,

Devilard³

et al. 1998

Br J Cancer

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Summary The Fas receptor (APO-1/CD95) is capable of inducing apoptosis of lymphoid cells and is expressed in some non-Hodgkin's lymphomas (NHLs). Fas expression is up-regulated at the surface of normal B cells upon triggering of the CD40 receptor. In this report, we investigated the sensitivity of NHLs to Fas-mediated apoptosis induced by anti-Fas monoclonal antibodies (MAbs) and its possible modulation by CD40 ligation in 18 NHL biopsy samples of various histological subtypes. Flow cytometric analysis showed that the fraction of Fas-expressing lymphoma cells was highly variable from sample to sample (from 1% to 93%, mean value 46%). The frequency of apoptotic cells was not significantly increased upon treatment with an anti-Fas MAb compared with control MAb in the 18 NHL cases analysed. The sensitivity of lymphoma cells to Fas-mediated apoptosis was correlated neither with the histological subtypes nor with the level of Fas expression. Activation of neoplastic B cells by CD40 ligation resulted in significant increases in Fas expression and Fas-induced apoptosis among the five B-NHL cases tested. The overall increase in apoptotic rates was moderate and remained lower in tumour samples than in control CD40-activated normal tonsil B cells. Altogether, our results indicate that the sensitivity to Fas-induced apoptosis is null or weak in NHL cells, irrespective of their histological subtype, and that it can be increased to a moderate and variable degree by CD40 ligation on neoplastic B cells. This may be an impediment to the development of Fas-based therapies for NHLs.Keywords: Fas; CD95; apoptosis; CD40; non-Hodgkin's lymphoma; Apo2.7 antibody; 7A6 antigen Dysregulation of programmed cell death, or apoptosis, can lead to aberrant cell accumulation and is recognized as a possible cause of neoplasia (Korsmeyer, 1992). The contribution of apoptosis is crucial in the pathogenesis of some non-Hodgkin's lymphomas (NHLs), such as follicular B-cell NHLs. In this particular NHL type, expression of the Bcl-2 antiapoptotic protein is increased in up to 85% of cases, because of a rearrangement of the BCL-2 gene (Bakhshi et al, 1985).The possible influence of apoptosis abnormalities on the growth of other NHL types is still debated. One of the major pathways regulating apoptosis in lymphoid cells appears to be mediated by the Fas antigen (APO-l/CD95), a 45-kDa membrane protein belonging to the tumour necrosis factor receptor (TNFR) superfamily (Itoh et al, 1991;Oehm et al, 1992;Armitage, 1994). Mice deficient in Fas or its ligand (FasL) are known as Ipr and gld mice respectively (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). They develop massive lymphadenopathy, splenomegaly, B-cell activation and autoimmunity owing to unscheduled lymphocyte accumulation (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). In addition, Fas has also been demonstrated to act as a tumoursuppressor gene in some particular conditions (Peng et al, 1996).Fas is expressed in various human lymphoproliferations (M6ller et al, 1993; Xerri et al, 1995a)...

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Section: Discussioncontrasting

confidence: 58%

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

Xerri

Bouabdallah²,

Devilard³

et al. 1998

Br J Cancer

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“…High Bcl-x(L)/Bcl-x(s) ratios are observed in a variety of cancer types, consistent with an important role for the long isoform in cancer cell survival (Xerri et al 1996;Olopade et al 1997;Takehara et al 2001). This likely reflects a reduction in Bcl-x(s) in cancer, as an examination of endometrial carcinomas showed a down-regulation of Bcl-x(s) mRNA compared with normal endometrial tissue, with the extent of Bcl-x(s) down-regulation correlated with clinical staging .…”

Section: Bcl-xmentioning

confidence: 59%

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

David

Manley²

2010

Genes Dev.

719

667

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Alternative splicing of mRNA precursors is a nearly ubiquitous and extremely flexible point of gene control in humans. It provides cells with the opportunity to create protein isoforms of differing, even opposing, functions from a single gene. Cancer cells often take advantage of this flexibility to produce proteins that promote growth and survival. Many of the isoforms produced in this manner are developmentally regulated and are preferentially re-expressed in tumors. Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.

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“…The present report suggests a specific antiapoptotic role of Bcl-xL in the apoptotic resistance of lymphoma cells, as we observed a lower level of Bcl-xL in normal B-cells, in accordance with our previous report. 37 Increased Bcl-xL levels were also reported in FL cells which survive upon CD40 stimulation. 38 Bax expression levels may be also an important parameter, as we found a significant difference between NHL cells and normal B cells.…”

Section: Discussionmentioning

confidence: 96%

Quantitative analysis detects ubiquitous expression of apoptotic regulators in B cell non-Hodgkin’s lymphomas

et al. 1999

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Predominant expression of the long isoform of Bcl‐x (Bcl‐xL) in human lymphomas

Cited by 90 publications

References 15 publications

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

Quantitative analysis detects ubiquitous expression of apoptotic regulators in B cell non-Hodgkin’s lymphomas

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