Clustered CD20 Induced Apoptosis: Src-Family Kinase, the Proximal Regulator of Tyrosine Phosphorylation, Calcium Influx, and Caspase 3-Dependent Apoptosis

Hofmeister, Joseph K.; Cooney, Damon S.; Coggeshall, K. Mark

doi:10.1006/bcmd.2000.0287

Cited by 199 publications

(159 citation statements)

References 35 publications

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“…There is controversy concerning the possible mechanisms of anti-CD20-induced cell death. Although some reports indicated that cell death induced by CD20 crosslinking has features of classical apoptosis, 17,[45][46][47] others were unable to confirm these findings. 17,27,48,49 A number of findings in our study strongly suggest that rituximab-induced cell death is a form of nonclassical apoptosis.…”

Section: Discussionmentioning

confidence: 97%

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

et al. 2011

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In vitro CD40-stimulated chronic lymphocytic leukemia (CLL) cells are resistant to cytotoxic drugs. In sharp contrast, we here show that CD40 stimulation sensitizes CLL cells to rituximabmediated cell death. This increased sensitivity is specific for anti-CD20 treatment. Rituximab-mediated death in CD40-stimulated CLL cells shows rapid kinetics (within hours), and is caspase and p53 independent, but depends on extracellular Ca 2 þ and reactive oxygen species (ROS) production. By increasing basal ROS production, CD40 stimulation sensitizes CLL cells to rituximab-mediated death. Our findings provide a rationale for combination treatment of CLL with cytotoxic drugs and anti-CD20 monoclonal antibodies.

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Section: Discussionmentioning

confidence: 97%

CD40 stimulation sensitizes CLL cells to rituximab-induced cell death

et al. 2011

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“…33,34 Previously, we demonstrated an indirect association between CD20 and src family kinases, 35,36 and recently discussed evidence that this is a result of mutual association with lipid rafts. 37 Src family kinase-dependent apoptotic signals can ensue from CD20 crosslinking 38,39 and this has been proposed to account for some of the efficacy of rituximab, a CD20-specific antibody used in treating B-cell cancers and some autoimmune diseases. 40 It is likely that CD20 crosslinking activates src kinases as a consequence of lipid raft aggregation.…”

Section: Discussionmentioning

confidence: 99%

A cholesterol-dependent CD20 epitope detected by the FMC7 antibody

et al. 2003

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Accurate diagnosis of lymphoid malignancies is essential for appropriate therapeutic intervention. In conjunction with other diagnostic determinants, immunophenotypic analysis of differentially expressed cell surface markers, such as CD5, CD20, CD23 and FMC7, is useful in the subclassification of lymphomas and leukemias arising from the B-cell lineage. Recent evidence suggesting that CD20 predicts FMC7 expression has prompted reappraisal of the utility of monitoring both markers. Here, we report that the FMC7 monoclonal antibody (mAb) specifically and strongly recognized CD20 ectopically expressed in hematopoietic and nonhematopoietic cell lines. The reactivity of FMC7 was abolished by mutations in the extracellular domain of CD20. These data confirm the CD20 specificity of FMC7. Like other CD20 mAbs, FMC7 binding was temperature dependent and induced detergent insolubility of CD20. Of significant interest, the CD20 epitope recognized by FMC7 was unusual in that it was exceptionally sensitive to membrane cholesterol. Cholesterol depletion profoundly reduced expression of the FMC7 epitope, whereas cholesterol enrichment enhanced its expression. FMC7 mAb binding thus appears to be a sensitive indicator of the level of plasma membrane cholesterol and reveals a conformational state of CD20 that is regulated by cholesterol.

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“…The pleiotropic effects of PLC-g including MAP kinase activation and specifically JNK, ERK and p38MAPK have been implicated in rituximab signaling (Pedersen et al, 2002). PLC-g also cleaves PIP 3 , generating inositol triphosphate and a resultant calcium flux, the latter being implicated in CD20-mediated apoptosis by the observation that intracellular and extracellular calcium chelation each inhibited apoptosis induced by anti-CD20 antibody in RAMOS cells (Hofmeister et al, 2000). Calcium flux could also relate to the direct effects of CD20 as a calcium channel.…”

Section: Cd20 Binding As a B-cell Signalmentioning

confidence: 99%

“…The extent of intracellular signal transduction, at least in some systems, can also be affected by the clustering of CD20 (Hofmeister et al, 2000). This may be dependent on the density of CD20 and the amount of antibody present.…”

Section: Cd20 Binding As a B-cell Signalmentioning

confidence: 99%