A complex interaction of different processes play a critical role in the development of hematopoietic lineages, and dysfunction of these interactions are directly involved in the pathogenesis of many types of human leukemia. The overall goal of this program is to study how these interacting factors direct normal hematopoiesis, and how abnormalities lead to leukemias. We will specifically focus on important hematopoietic transcription factors, fusion peptides found in leukemias as a result of translocations, the signaling pathways which affect these proteins, and their effect on alteration of defined hematopoietic precursor subsets. The future aims are to use this knowledge to design specific therapies for treatment of hematopoietic malignancies. The specific projects will include the following proposals: (1) C/EBP alpha signaling and regulation in myelopoiesis and leukemia; (2) C/EBP alpha and PU.1 in Normal and Malignant Hematopoiesis; (3) RUNX1 in Myeloid Development; and (4) The role of JNK signaling pathways in leukemia. The administrative core shall be responsible for many interactive functions of the program, including regular meetings, seminars, and communication among projects. By combining a variety of approaches, including studies of transcriptional regulation, protein-protein interactions, phosphorylation and signal transduction, knockout and knock-in mice, and structure-function relationships, we will provide new information concerning a very interesting group of proteins whose functions and interactions are directly related to hematopoiesis and leukemogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA072009-07
Application #
6749005
Study Section
Subcommittee G - Education (NCI)
Program Officer
Mufson, R Allan
Project Start
1997-09-15
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
7
Fiscal Year
2004
Total Cost
$1,534,395
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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Radomska, Hanna S; Basseres, Daniela S; Zheng, Rui et al. (2006) Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J Exp Med 203:371-81
Iwasaki, Hiromi; Mizuno, Shin-ichi; Arinobu, Yojiro et al. (2006) The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 20:3010-21
Peterson, Luke F; Boyapati, Anita; Ranganathan, Velvizhi et al. (2005) The hematopoietic transcription factor AML1 (RUNX1) is negatively regulated by the cell cycle protein cyclin D3. Mol Cell Biol 25:10205-19
Opferman, Joseph T; Iwasaki, Hiromi; Ong, Christy C et al. (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101-4
Biggs, Joseph R; Zhang, Youhong; Peterson, Luke F et al. (2005) Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association. Mol Cancer Res 3:391-401
Iwasaki, Hiromi; Somoza, Chamorro; Shigematsu, Hirokazu et al. (2005) Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106:1590-600
Koschmieder, Steffen; Rosenbauer, Frank; Steidl, Ulrich et al. (2005) Role of transcription factors C/EBPalpha and PU.1 in normal hematopoiesis and leukemia. Int J Hematol 81:368-77
Zhang, Pu; Iwasaki-Arai, Junko; Iwasaki, Hiromi et al. (2004) Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity 21:853-63
Ross, Sarah E; Radomska, Hanna S; Wu, Bo et al. (2004) Phosphorylation of C/EBPalpha inhibits granulopoiesis. Mol Cell Biol 24:675-86

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