Genetic Modifiers of the Anti-apoptotic Functions of Bcl-2

Dana-Farber Cancer Inst, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): [unreadable] This proposal is designed to provide the candidate a period of mentored research in the laboratory of Dr. A. T. Look, a pioneer in the field of hematopoietic malignancies and the use of zebrafish as a model system to study these diseases. The goal of this application is to use the zebrafish as a model to study novel genes and pathways necessary for the anti-apoptotic functions of Bcl-2, a gene whose aberrant expression is highly associated with follicular B-cell lymphoma and other hematological malignancies. The zebrafish, with its close synteny to the human genome and its conserved molecular pathways regulating the development of tissues and organs, offers a powerful tool with which to conduct such research. A transgenic zebrafish line that specifically expresses an EGFP-tagged zbcl-2 fusion protein in lymphoid cells has been employed in a genetic modifier screen, and the candidate has identified four zebrafish mutant lines that demonstrate suppression of the anti-apoptotic functions of Bcl-2 in vivo. The underlying hypothesis is that knowledge of the zebrafish genes able to suppress Bcl-2-mediated apoptosis in lymphoid cells with damaged DNA will implicate novel pathways through which human BCL-2 exerts its anti-apoptotic activity in cancer cells. In Aim 1, the mutated genes will be mapped and positionally cloned. Mutations will be analyzed using a rag2-EGFP-mMyc zebrafish model of T-ALL to determine their ability to resensitize Bcl-2-expressing leukemic T cells to radiation-induced cell death. In Aim 2, functional and molecular analyses will be used to investigate the mechanisms by which each mutant gene suppresses the function of Bcl-2. The long-term goal of this application is to restore normal cell death pathways in B-cell follicular lymphoma and other hematological cancers by targeting pivotal molecules with small molecule inhibitors or antibodies. [unreadable] As part of their regulated life cycle, normal cells undergo programmed cell death (apoptosis) in response to DNA damage. Cancer cells derived from B-cell follicular lymphoma, as well as many other blood diseases, have aberrantly high levels of Bcl-2, a protein that causes cell survival in the face of apoptosis-inducing cancer therapies. The goal of this application is to use the zebrafish model system to identify targets for small molecule inhibitors of Bcl-2 function in order to restore normal cell death pathways in cancer cells. [unreadable] [unreadable]