Specific chromosomal translocations are associated with a number of hematologic malignancies. Several of these have been demonstrated to result in the activation of an oncogene. How an oncogene becomes activated by a translocation that does not affect its coding sequence is not known and is a central question in cancer research. This proposal will attempt to answer that question for the BCL-2 oncogene. In lymphomas with the t(14;18) translocation, the BCL-2 gene is translocated to the immunoglobulin locus. Because the immunoglobulin gene is active in B cells, a reasonable hypothesis is that the translocation somehow activates BCL-2, this is one step along the way to development of the malignant phenotype. The applicant proposes to study the mechanism of activation at a molecular level in human lymphoma tissue. The activation of the translocated BCL-2 gene will be compared to the transcriptional regulation of the normal BCL-2 gene during B-cell development and during B-cell activation. The goal is to reach a better understanding of the mechanisms of malignant transformation.
The specific aims are: A) determination of the role of CREB in the regulation of BCL-2 in normal B cells; B) determination of the role of other transcription factors in modifying the activity of CREB on the BCL-2 promoter in normal B cells; C) determination of the role of CREB, WT1, pi1, p53, the URE factor, Myb and the immunoglobulin enhancers in the deregulation of the translocated BCL-2 gene in t(14;18) lymphomas; D) creation of a model system of the t(14;18) translocation to test the hypotheses for the deregulation of BCL-2. The successful completion of this proposal will represent the first instance where the molecular mechanisms involved in the transcriptional activation of an oncogene by translocation are known. The transcription factors that are required for the activation of expression of BCL-2 will be identified, and the region of the immunoglobulin locus that are responsible for this will be characterized.
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