Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026038-26
Application #
6710690
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
1979-07-01
Project End
2008-02-28
Budget Start
2004-03-17
Budget End
2005-02-28
Support Year
26
Fiscal Year
2004
Total Cost
$363,052
Indirect Cost

  Institution

Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048

  Publications

Sun, Q-Y; Ding, L-W; Tan, K-T et al. (2017) Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD). Leukemia 31:1-10
Ding, L-W; Ikezoe, T; Tan, K-T et al. (2017) Mutational profiling of a MonoMAC syndrome family with GATA2 deficiency. Leukemia 31:244-245
Ding, Ling-Wen; Sun, Qiao-Yang; Tan, Kar-Tong et al. (2017) Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia. Cancer Res 77:390-400
Madan, V; Shyamsunder, P; Han, L et al. (2016) Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Leukemia 30:1672-81
Cao, Q; Gearhart, M D; Gery, S et al. (2016) BCOR regulates myeloid cell proliferation and differentiation. Leukemia 30:1155-65
Sun, Haibo; Lin, De-Chen; Guo, Xiao et al. (2016) Inhibition of IRE1?-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia. Oncotarget 7:18736-49
Nowak, Daniel; Liem, Natalia L M; Mossner, Maximilian et al. (2015) Variegated clonality and rapid emergence of new molecular lesions in xenografts of acute lymphoblastic leukemia are associated with drug resistance. Exp Hematol 43:32-43.e1-35
Madan, Vikas; Kanojia, Deepika; Li, Jia et al. (2015) Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome. Nat Commun 6:6042
Garg, Manoj; Okamoto, Ryoko; Nagata, Yasunobu et al. (2015) Establishment and characterization of novel human primary and metastatic anaplastic thyroid cancer cell lines and their genomic evolution over a year as a primagraft. J Clin Endocrinol Metab 100:725-35
Garg, Manoj; Nagata, Yasunobu; Kanojia, Deepika et al. (2015) Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood 126:2491-501

Showing the most recent 10 out of 226 publications