Blood cell development, or hematopoiesis, generates a variety of distinct cell lineages including lymphocytes, erythrocytes, megakaryocytes, monocytes, and granulocytes. These cells perform a diverse array of biological functions: they secrete antibodies, display cytotoxicity for tumor cells, transport molecular oxygen, synthesize and export growth factors, and destroy pathogens. Although the molecular mechanisms underlying hematopoietic development have not been completely resolved, it is clear that lineage-specific transcription factors are critical to this process. PU.1 (Spi-1) and Spi-B are highly related proteins that represent a subgroup of the Ets family of transcription factors. Ets factors have been studied extensively as key regulators of cellular differentiation and oncogenesis. By generating null mutations in mice, we have shown that both PU.1 and Spi-B are essential to hematopoiesis. PU.1 plays an unanticipated role in the proliferation, survival, and differentiation of multi- potential lymphoid-myeloid progenitors. This results in a complete loss of B cells, T cell macrophages, and neutrophils in PU.1-/- mutant mice. In direct contrast, Spi-B is dispensable for blood cell development but crucial for B lymphocyte expansion and antibody secretion upon stimulation of the B cell receptor (BCR) by antigen binding. In the studies described in this application, we will use a combination of biochemical and genetic approaches to precisely define their unique roles in blood cell development and/or function. Specifically, we will (i) determine why PU.1 is essential for proliferation and differentiation of lymphoid-myeloid progenitors, (ii) study how the transcriptional activity of PU.1 is regulated during lymphopoiesis and myelopoiesis, (iii) determine how Spi-B transcriptional activity is regulated in mature B cells, (iv) determine the extent to which PU.1 and Spi-B play redundant roles during hematopoiesis, and (v) characterize the BCR signaling defect that leads to apoptosis of PU.1+/- Spi-B+/- lymphocytes. These studies will have important implications for our understanding of how related transcription factors promoter different aspects of blood cell maturation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Dahl, Richard; Walsh, Jonathan C; Lancki, David et al. (2003) Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPalpha ratio and granulocyte colony-stimulating factor. Nat Immunol 4:1029-36
Perkel, Jeffrey M; Simon, M Celeste; Rao, Anjana (2002) Identification of a c-myb attenuator-binding factor. Leuk Res 26:179-90
Heydemann, A; Warming, S; Clendenin, C et al. (2000) A minimal c-fes cassette directs myeloid-specific expression in transgenic mice. Blood 96:3040-8
Rao, S; Matsumura, A; Yoon, J et al. (1999) SPI-B activates transcription via a unique proline, serine, and threonine domain and exhibits DNA binding affinity differences from PU.1. J Biol Chem 274:11115-24
Fisher, R C; Olson, M C; Pongubala, J M et al. (1998) Normal myeloid development requires both the glutamine-rich transactivation domain and the PEST region of transcription factor PU.1 but not the potent acidic transactivation domain. Mol Cell Biol 18:4347-57
Thirman, M J; Diskin, E B; Bin, S S et al. (1997) Developmental analysis and subcellular localization of the murine homologue of ELL. Proc Natl Acad Sci U S A 94:1408-13
Heydemann, A; Boehmler, J H; Simon, M C (1997) Expression of two myeloid cell-specific genes requires the novel transcription factor, c-fes expression factor. J Biol Chem 272:29527-37
Peters, L L; Ciciotte, S L; Su, G H et al. (1997) The gene encoding the transcription factor Spi-B maps to mouse chromosome 7. Mamm Genome 8:452-3
Chutkow, W A; Simon, M C; Le Beau, M M et al. (1996) Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 45:1439-45
Heydemann, A; Juang, G; Hennessy, K et al. (1996) The myeloid-cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor. Mol Cell Biol 16:1676-86

Showing the most recent 10 out of 14 publications