The molecular immunology studies continue to be directed at the cloning and characterization of new B cell genes. The ultimate aim of these studies is the identification of master regulator genes which control the activation and expression of B cell genes in development. It is likely that such genes which act early in differentiation will play a critical role in influencing the development of stem cells into B cells. The studies in this renewal application build on the successful characterization of the transcription control elements which regulate two genes cloned in this project. (i.e., B29, pp52), both of which are expressed from the earliest stages in B cell development. A critical GATA motif identified in the B29 5' enhancer binds a B cell specific factor which is a compelling candidate for a master regulator. Cloning and characterization of this B cell-specific GATA-binding factor, along with other new tissue-specific factors which regulate B29 gene transcription, are the highest priorities of these studies (Aim #1). The pp52/s37 gene contains two widely-separated tissue-specific promoters which regulate the expression of alternative mRNA species in lymphoid cells versus stromal cells. Studies to completely define these different tissue-specific promoters and to resolve the interactions of the lymphoid and stromal cell gene products with cell surface molecules and the cytoskeleton comprise( AIM#2). Both the human B29 and pp52 genes map to loci that are recurrently and nonrandomly translocated in human chronic lymphocytic leukemia (CLL) cells. CLL is predominantly a B cell leukemia in which the assembly and/or activity of cell surface antigen receptor complexes appear to be impaired. This feature strongly suggests that alterations in B29 or other genes (e.g., mb-1) required for B cell antigen receptor complex assembly and function may be affected in CLL. The extensive characterization of these B cell genes provides a powerful advantage for identifying chromosomal translocations in CLL (AIM #3). These related lines of research are expected to establish new understanding of the regulation of B cell gene activation and the early events in B cell development. They also directly address the nature and activity of translocated B cell genes in human chronic lymphocytic leukemia.
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