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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. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-11-124487v1 112/8/3312    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stolz, C. Articles by Schuler, M. Search for Related Content PubMed PubMed Citation Articles by Stolz, C. Articles by Schuler, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 16, 2007 Accepted July 27, 2008 Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to Rituximab-induced apoptosis Claudia Stolz, Georg Hess, Patricia S. Hahnel, Florian Grabellus, Sandra Hoffarth, Kurt W. Schmid, and Martin Schuler* Department of Medicine (Cancer Research), University Hospital Essen, Essen, Germany Department of Medicine III, Johannes Gutenberg University, Mainz, Germany Department of Pathology and Neuropathology, University Hospital Essen, Essen, Germany * Corresponding author; email: martin.schuler{at}uk-essen.de. The chimeric monoclonal antibody Rituximab is standard of care for patients suffering from B-cell Non-Hodgkin's lymphoma (B-NHL). Rituximab mediates complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) of CD20-positive human B cells. In addition, Rituximab sensitizes B-NHL cells to cytotoxic chemotherapy, and has direct apoptotic and antiproliferative effects. While 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 anti-apoptotic 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 anti-apoptotic Bcl-2 family proteins, or activation of phosphatidylinositol-3-kinase (PI3K) signaling resulting in upregulation of Mcl-1. The former resistance pattern is overcome by treatment with the BH3-mimetic ABT-737, the latter by combining Rituximab with pharmacologic PI3K 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. A. Johnson, K. J. Savage, O. Ludkovski, S. Ben-Neriah, R. Woods, C. Steidl, M. J. S. Dyer, R. Siebert, J. Kuruvilla, R. Klasa, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival Blood, September 10, 2009; 114(11): 2273 - 2279. [Abstract] [Full Text] [PDF]

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