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.

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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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Nasseri, M Faraz
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University of Pennsylvania
Schools of Medicine
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Banerjee, Anupam; Northrup, Daniel; Boukarabila, Hanane et al. (2013) Transcriptional repression of Gata3 is essential for early B cell commitment. Immunity 38:930-42
Wolf, Amaya I; Mozdzanowska, Krystyna; Quinn 3rd, William J et al. (2011) Protective antiviral antibody responses in a mouse model of influenza virus infection require TACI. J Clin Invest 121:3954-64
Thomas, Matthew; Calamito, Marco; Srivastava, Bhaskar et al. (2007) Notch activity synergizes with B-cell-receptor and CD40 signaling to enhance B-cell activation. Blood 109:3342-50
Lindsley, Robert Coleman; Thomas, Matthew; Srivastava, Bhaskar et al. (2007) Generation of peripheral B cells occurs via two spatially and temporally distinct pathways. Blood 109:2521-8
Allman, David; Dalod, Marc; Asselin-Paturel, Carine et al. (2006) Ikaros is required for plasmacytoid dendritic cell differentiation. Blood 108:4025-34
Harman, Benjamin C; Miller, Juli P; Nikbakht, Neda et al. (2006) Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors. Blood 108:878-85
Srivastava, Bhaskar; Quinn 3rd, William J; Hazard, Kristin et al. (2005) Characterization of marginal zone B cell precursors. J Exp Med 202:1225-34
Miller, Juli P; Allman, David (2003) The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 171:2326-30
Allman, David; Sambandam, Arivazhagan; Kim, Sungjune et al. (2003) Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4:168-74
Miller, Juli P; Izon, David; DeMuth, William et al. (2002) The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. J Exp Med 196:705-11