Macrophages play an essential role in host defense: they ingest and kill pathogens, process and present antigens to lymphocytes, and secrete functionally diverse cytokines. Patients lacking healthy phagocytic cells, such as macrophages and neutrophils, exhibit a lethal susceptibility to infection by microbes. Monocytes display an important cytotoxic activity for tumor cells in breast, lung, and gastrointestinal cancers. However, little is known about the molecular mechanisms controlling myeloid cell (macrophage and neutrophil) development. The proto-oncogene Spi-1 and a related gene, Spi-B, are the first examples of lineage-restricted transcription factors implicated in gene regulation in myeloid cells. Using a genetic approach, involving mouse embryonic stem cells and mutant myeloid cell lines, we will assess the role of Spi-1 and Spi-B in myeloid cell development and gene expression. We will also learn what roles they play in the production of other hematopoietic cells. Spi-1 causes erythroleukemias when aberrantly expressed in red cell precursors. We will show which known myeloid- specific genes are downstream targets for Spi-1 and ascertain if they are involved in erythroleukemogenesis. We will identify novel Spi-1-regulated genes and determine if they also function in Spi-1- induced oncogenesis. We will assess the regulation of a myeloid- specific gene, the c-fes proto-oncogene, by Spi-1 and Spi-B. We hope to identify and clone genes encoding other myeloid-specific nuclear regulatory proteins. The discovery of additional lineage- restricted myeloid transcription factors is necessary for a complete understanding of myeloid cell gene expression. These experiments are critical to a better description of the molecular events that produce myeloid cells from hematopoietic progenitor cells. The proposed studies are relevant both to normal hematopoietic (and specifically myeloid cell) development and to the molecular pathogenesis of hematopoietic neoplasia.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052094-04
Application #
2415621
Study Section
Pathology B Study Section (PTHB)
Project Start
1994-05-01
Project End
1998-11-30
Budget Start
1997-05-01
Budget End
1998-11-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
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