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

Item Type:Article
Title:Bcl-2 mediates chemoresistance in matched pairs of primary Emu-myc lymphomas in vivo
Creators Name:Schmitt, C.A. and Lowe, S.W.
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 Eμ-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 Eμ-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-MBcl-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 vivo.
Keywords:Apoptosis, bcl-2, Chemoresistance, Lymphoma, E{mu}-myc mouse, Animals, Mice
Source:Blood Cells Molecules and Diseases
Page Range:206-216
Date:January 2001
Official Publication:https://doi.org/10.1006/bcmd.2000.0372
PubMed:View item in PubMed

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