Bcl-2 mediates chemoresistance in matched pairs of primary E mu-myc lymphomas in vivo

Schmitt, C. A., Lowe, S. W. (January 2001) Bcl-2 mediates chemoresistance in matched pairs of primary E mu-myc lymphomas in vivo. Blood Cells Molecules and Diseases, 27 (1). pp. 206-216. ISSN 1079-9796

URL: http://www.ncbi.nlm.nih.gov/pubmed/11358381
DOI: 10.1006/bcmd.2000.0372

Abstract

The oncoprotein Bcl-2 is a potent survival factor antagonizing p53-dependent and -independent apoptotic cell death. Although many anticancer agents are known to engage apoptotic pathways, the clinical impact of Bcl-2 on treatment outcome remains controversial. Since it might be difficult to assess the contribution of a single gene to treatment response in patient material due to technical considerations, we sought to address Bcl-2's role in a mouse model of primary lymphomas treated at their natural site. Driven by the E mu -enhancer controlled c-myc transgene, primary B cell lymphomas arise in this model by several months of age and resemble closely typical clinical and histopathological features of human non-Hodgkin lymphomas. We introduced either bcl-2 or a control construct into identical samples of freshly isolated E mu -myc lymphomas by retroviral gene transfer in order to obtain matched pairs of primary lymphomas differing only in their Bcl-2 status. While no Bcl-2-mediated effect was detectable in clonogenic survival assays in vitro, treatment of the genetically modified lymphoma pairs propagated in nontransgenic recipient mice revealed Bcl-2's impact on drug sensitivity in vivo Bcl-2 efficiently blocked short- and long-term drug-mediated cell death in vivo. In a comparison of 15 matched pairs of primary lymphomas, the bcl-2 transduced sample never achieved longer remission periods than the control counterpart and most of the Bcl-2 overexpressing lymphomas failed to respond at all. We conclude that-when assessed in the physiological environmental context-Bcl-2 contributes to chemoresistance of B cell lymphomas in vivo This model, able to test any other candidate gene, will be particularly useful to study the implications of specific mutations for drug action in viva (C) 2001 Academic Press.

Item Type: Paper
Uncontrolled Keywords: apoptosis Bcl-2 chemoresistance lymphoma E mu-myc mouse NON-HODGKINS-LYMPHOMA CLONOGENIC SURVIVAL DRUG-RESISTANCE PROGNOSTIC-SIGNIFICANCE PROTEIN EXPRESSION INDUCED APOPTOSIS BREAST-CANCER P53 GENE CELLS LEUKEMIA
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies > chemoresistance
diseases & disorders > cancer > cancer types > lymphoma
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: January 2001
Date Deposited: 16 Jan 2014 16:23
Last Modified: 16 Jan 2014 16:23
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29298

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