A number of lymphoid malignancies are associated with specific chromosomal translocations. Many of these translocations result in the activation of an oncogene. The majority of low-grade follicular lymphomas have a t(14; 18) with translocation of the bcl-2 gene to the immunoglobulin heavy chain locus. Bcl-2 expression is deregulated in these lymphomas, presumably due to the influence of the immunoglobulin enhancers, although the molecular mechanisms of the deregulation are not understood.We propose to examine the molecular mechanisms involved in the deregulation of the translocated bcl-2 gene using several model systems. We postulate that the IgH enhancers maintain the bcl-2 promoter in an open transcriptional conformation through the recruitment of histone acetylases allowing the binding of transcription factors to the promoter. Interference with the function of the most active transcription factor(s) should therefore decrease bcl-2 expression. Studies will be performed to test these assumptions. The most active elements of the immunogiobulin heavy chain enhancers will be characterized, and the elements of both the 5' and 3' bcl-2 promoters that interact with them will be defined. The regulation of the normal bcl-2 gene in B cells will also be studied and compared to that of the translocated and untranslocated bcl-2 genes. A mouse model of the translocation will be made to gain further insight into the mechanisms involved in the deregulation of the bcl-2 gene. Strategies to interfere with transcription factor function will be developed to decrease bcl-2 expression in cells with deregulated expression. 1. Elucidation of the role of the CRE and CDX sites in the regulation of bcl-2 expression in B cells without the t(14;18). We have determined that these sites bind several transcription factors that are critical for bcl-2 regulation. 2. Mechanisms involved in deregulation of the translocated bcl-2 allele. a. Elucidation of the molecular mechanisms involved in deregulation of the bcl-2 promoter in t(14; 18) lymphomas: role of the CRE and CDX sites. b. Determination of the role of the IgH enhancers in the deregulation of expression of bcl-2. The most active site in each enhancer will be studied. 3. Construction of a mouse model to study the deregulation of bcl-2 by the 3' immunoglobulin heavy chain enhancers. Molecular studies will be performed to determine the mechanisms involved in deregulation of bcl-2, and methods will be developed to interfere with bcl-2 activation. We will attempt to create a mouse model of the t(14;18) lymphoma.These studies should provide the groundwork for the development of novel therapies for future therapeutic trials in lymphomas with deregulated bcl-2 expression.
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