Transcription factors are the engines driving proliferation and differentiation of hematopoietic progenitor cells. We focus on one family of transcription factors known as C/EBP, and in particular C/EBPepsilon.
Specific Aim 1 will identify the downstream target genes of C/EBPepsilon using three model systems: 1.) C/EBPepsilon deletional (-/-) mice. 2.) Cells from individuals with specific granule deficiency (SGD). These individuals have germline mutations of C/EBPepsilon. 3.) Myeloid cell lines established from C/EBP-/- mice.
Specific Aim 2 will focus on CXP1 which is a new member of a family of proteins that we discovered; it is a transcriptional target of C/EBPepsilon. The structure suggests that CXR1 is a secreted protein that may have anti-microbiocidal activity.
Specific Aim 3 will identify proteins that interact with C/EBPepsilon including C/EBPzeta and PIAS1. We will study the function of these interacting proteins.
Specific Aim 4 will determine the amino acids of C/EBPepsilon which undergo changes in phosphorylation in response to signaling by growth or differentiation factors and how these modifications affect function.
Specific Aim 5 will attempt to use C/EBPalpha and -epsilon for differentiation therapy of acute myelogenous leukemia (AML). We and others have shown that forced expression of either C/EBPalpha or C/EBPepsilon can """"""""short circuit"""""""" the panoply of genetic defects in human AML cell lines and induce these cells to undergo terminal differentiation. We are developing unique methods to deliver abundant C/EBPalpha and -epsilon to AML cells.
Specific Aim 6 will study myelopoiesis using a variety of C/EBP deletional mice and their hybrids. Myeloid cell lines will be established from them. The mice and cell lines will provide excellent models to study the contribution of each member of the C/EBP family to regulate hematopoiesis.
Specific Aim 7 briefly outlines several additional projects: A.) Chromatin immunoprecipitation assays will identify which C/EBPs are important in transactivation of target genes in vivo and will identify C/EBPepsilon target genes. B.) Antiproliferative effects of C/EBPepsilon independent of its ability to be a transcriptional factor will be explored. C.) A comparative analysis of genes regulated by PML/RAR and PLZF/RAR +/- retinoic acid in myeloid leukemia cells will be pursued. D.) Defects of T-lymphocytes in C/EBPepsilon -/- mice will be investigated. Taken together, our studies should provide a firm understanding of the role of C/EBPepsilon and other C/EBP family members in hematopoiesis.
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