EBF1 is a crucial regulator of B lymphocyte lineage specification and commitment. In mice lacking EBF1 (encoded by the Ebf1 gene), B cell development is arrested and immunoglobulins (Ig) are not produced. Recently, we determined that mice with a single wild type Ebf1 allele (Ehet mice) exhibit defects in B cell development in the bone marrow. B cell development is further impaired in Ehet mice that also possess a single functional Runx1 (Rhet) allele. Runx1 encodes the Runt domain transcription factor Runx1 (CBF12/PEBP21), a functional partner of EBF1. In single Ehet and double (ERhet) haploinsufficient mice, we observed 1) substantially decreased numbers of CD19+ cells in the bone marrow, 2) delayed activation of pre-B cell markers, 3) reduced levels of Ig;light (L) chain rearrangements and 4) the loss of B cell identity, as evidenced by the mixing of B cell and NK cell phenotypes. The loss of B cell identity occurred in the presence of Pax5, a defined mediator of B cell commitment. We will address the central hypothesis that EBF1 is a primary regulator of B cell lineage specification and commitment. We propose that 1) the appropriate dosage of EBF1 is critical for establishing B cell identity and progression, and 2) this role of EBF1 is dependent on its functions as a transcriptional repressor, which is an undefined mechanism. We will continue our studies by identifying signaling defects in pro-B/pre-B cells that express reduced levels of EBF1. In the last aim, we will address whether EBF1 is required for the maintenance of B cell identity by utilizing new Ebf1 conditional knockout (Ecko) mice developed in our laboratory. Together, these studies will result in important new insights concerning functions of EBF1 in the regulation of B cell lineage specification, commitment and progression.

Public Health Relevance

Early B cell Factor (EBF1) is essential for the production of B lymphocytes, which produce antibodies in response to foreign pathogens. Here, we will determine how EBF1 regulates the development of these cells in bone marrow. We will also address how EBF prevents the expression of genes of other types of hematopoietic cells, resulting in the commitment of progenitors to become B cells. Our studies are important for understanding how EBF controls these processes in normal cells, autoimmune diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081878-05
Application #
8605152
Study Section
Special Emphasis Panel (ZRG1-IMM-H (02))
Program Officer
Nasseri, M Faraz
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$386,100
Indirect Cost
$138,600
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Dege, Carissa; Hagman, James (2014) Mi-2/NuRD chromatin remodeling complexes regulate B and T-lymphocyte development and function. Immunol Rev 261:126-40
Collins, Bernard; Clambey, Eric T; Scott-Browne, James et al. (2013) Ikaros promotes rearrangement of TCR * genes in an Ikaros null thymoma cell line. Eur J Immunol 43:521-32
Dege, Carissa; Hagman, James (2013) Activation of Aicda gene transcription by Pax5 in plasmacytoma cells. Immunol Res 55:155-61
Hagman, James; Lukin, Kara (2013) Plasma cells for hire: prior experience required. Immunity 39:89-91
Wang, Meiqin; Ramirez, Julita; Han, Junyan et al. (2013) The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis. J Allergy Clin Immunol 132:1174-1183.e8
Musselman, Catherine A; Ramírez, Julita; Sims, Jennifer K et al. (2012) Bivalent recognition of nucleosomes by the tandem PHD fingers of the CHD4 ATPase is required for CHD4-mediated repression. Proc Natl Acad Sci U S A 109:787-92
Hagman, James; Ramirez, Julita; Lukin, Kara (2012) B lymphocyte lineage specification, commitment and epigenetic control of transcription by early B cell factor 1. Curr Top Microbiol Immunol 356:17-38
Lukin, Kara; Fields, Scott; Guerrettaz, Lisa et al. (2011) A dose-dependent role for EBF1 in repressing non-B-cell-specific genes. Eur J Immunol 41:1787-93