Mechanisms of Lymphoid Lineage Commitment

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): How transcription factors regulate lineage choice decisions in lymphocyte development remains unclear. The main objective of this competitive renewal application is to evaluate the role the EBF transcription factor in early B cell development with a strong emphasis on the role of EBF in restricting multipotent precursors to the B cell fate. The main hypothesis guiding this work is that EBF plays a nonredundant and critical role in establishing and maintaining B cell commitment. This model differs from current views of B-lineage commitment, which state that B-lineage restriction is directly regulated by two alternative transcription factors known as E2a and Pax5. In contrast my model predicts that E2a and Pax5 regulate B-lineage commitment indirectly by promoting EBF expression. To test this model we will: 1) Define the role of EBF in restricting multilineage differentiation;2) Define the role of the EBF-Pax5 and EBF-E2a regulatory loops in B-lineage restriction;and 3) Determine the functional relevance of proposed EBF repressive targets. These studies will provide fundamental information on the mechanisms underpinning early B cell differentiation and B-lineage commitment. PUBLIC HEALTH RELEVANCE: How transcription factors regulate lineage choice decisions in lymphocyte development remains unclear. These studies will elucidate the role of specific transcription factors in regulating early B cell differentiation. The resulting data will provide fundamental information with application to several disease states including bone marrow transplantation in cancer patients and the manipulation of B cell development in immunodeficiency and autoimmunity.