): Normal function of the immune system requires the differentiation of pluripotent stem cells into mature lymphoid cells. Abnormalities in this process can lead to the development of leukemias and lymphomas. The differentiation and proliferation of cells of the immune system often occur in response to external stimuli, such as antigens or growth substances. This response requires that the receptors on the surface of these cells recognize the stimulus and initiate a series of signal transduction events. These signals are necessary for both developmental decisions and initiation of immune responses by B and T lymphocytes. One approach for analyzing the regulation of the immune system is to isolate transcription factors which regulate B cell specific genes. In particular, the investigators recently identified a novel member of the Ets transcription factor/oncogene family, NERF, from human spleen and fetal liver, which has a DNA binding domain which is highly homologous to the Ets factor ELF-1. ELF-1 has been implicated in the regulation of T cell-specific gene expression. The preliminary data demonstrate that NERF and ELF-1 are highly expressed in B cells and interact with the same regulatory elements of a whole set of B cell-specific genes including blk, lyn, TdT, mb-1, B29 and the Igh pi site. Many of these genes are differentially regulated during B cell development. Furthermore, disruption of the function of some of the transcription factors which regulate the expression of these genes such as BSAP and EBF results in marked abnormalities in B cell differentiation and function. NERF and ELF-1 appear to have the highest binding affinity for the promoter regions of the lyn and blk tyrosine kinase genes. Both lyn and blk are required for normal signal transduction of the activated antigen/receptor complex on B lymphocytes. The hypothesis for the proposed studies is that, because NERF and ELF-1 bind with high affinity to the regulatory regions in the promoters of a number of B cell specific genes, they are critical for B cell function and differentiation. They may have opposing effects, one upregulating gene expression and the other downregulating it. They may be redundant and have similar effects; or one may be more active than the other in certain cell types or at certain development stages. To further elucidate the role of ELF-1 and NERF in B cell development and function the goals of this project are to determine their expression at different stages of B cell development, demonstrate their ability to function as transcription factors in regulating B cell specific genes, and determine the effect on immune system function and development when these genes are disrupted.
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