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 Blood, 15 October 2008, Vol. 112, No. 8, pp. 3312-3321.
Prepublished online as a Blood First Edition Paper on August 8, 2008; DOI 10.1182/blood-2007-11-124487.

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NEOPLASIA

Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis

Claudia Stolz1, Georg Hess2, Patricia S. Hähnel1, Florian Grabellus3, Sandra Hoffarth1, Kurt W. Schmid3, and Martin Schuler1

1 Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Essen; 2 Department of Medicine III, Johannes Gutenberg University, Mainz; and 3 Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, Essen, Germany

The chimeric monoclonal antibody rituximab is the standard of care for patients with B-cell non-Hodgkin lymphoma (B-NHL). Rituximab mediates complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity of CD20-positive human B cells. In addition, rituximab sensitizes B-NHL cells to cytotoxic chemotherapy and has direct apoptotic and antiproliferative effects. Whereas expression of the CD20 antigen is a natural prerequisite for rituximab sensitivity, cell-autonomous factors determining the response of B-NHL to rituximab are less defined. To this end, we have studied rituximab-induced apoptosis in human B-NHL models. We find that rituximab directly triggers apoptosis via the mitochondrial pathway of caspase activation. Expression of antiapoptotic Bcl-xL confers resistance against rituximab-induced apoptosis in vitro and rituximab treatment of xenografted B-NHL in vivo. B-NHL cells insensitive to rituximab-induced apoptosis exhibit increased endogenous expression of multiple antiapoptotic Bcl-2 family proteins, or activation of phosphatidylinositol-3-kinase signaling resulting in up-regulation of Mcl-1. The former resistance pattern is overcome by treatment with the BH3-mimetic ABT-737, the latter by combining rituximab with pharmacologic phosphatidylinositol-3-kinase inhibitors. In conclusion, sensitivity of B-NHL cells to rituximab-induced apoptosis is determined at the level of mitochondria. Pharmacologic modulation of Bcl-2 family proteins or their upstream regulators is a promising strategy to overcome rituximab resistance.


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