The long-term goal of this study is to understand the role of transcription factors in normal hematopoiesis and leukemia. Transcription factor AML1 (acute myeloid leukemia factor 1) has been identified from chromosomal translocation t(8;21) acute myeloid leukemia (AML) patients that express the AML/ETA fusion protein. This is the most common form of AML1/MDS have been reported in pre-Beta acute lymphoid leukemia (ALL) patients with t(12;21), in blast crisis patients of chronic myeloid leukemia (CML) and in patients of myelodysplastic syndrome (MDS) progressing to AML with t(3;21), respectively. These data indicate the importance of transcription factor AML1 in normal hematopoiesis and in the development of leukemia. Therefore, understanding the mechanism of AML1 in development of normal hematopoiesis and in the development of leukemia. Therefore, understanding the mechanism of AML1 in development of normal blood cells and leukemia will help us gain more information about leukemogenesis and suggest possible therapeutic treatments for leukemia patients in the future. We have reported that AML1 regulates the expression of the receptor for a critical hematopoietic growth factor, macrophage colony stimulating factor (M-CSF or CSF-1). The abnormal over expression of the M-CSF receptor has been directly related to cell transformation and leukemia. In addition, we have shown in this proposal that AML1 can bind to regulatory sequences of two Beta-cell specific genes, blk (Beta lymphocyte protein tyrosine kinase) and immunoglobulin heavy chain. Both these two gene products play critical role for the proliferation and differentiation of Beta cells. Most recently our AML1-ETO knock-in mice analysis suggests that AML1-ETO block normal AML1 function during hematopoiesis. However, AML1-ETO may play additional roles besides blocking normal AML1 function during hematopoiesis. The overall purpose of this proposal, then, is to study the function of AML1 and its fusion protein AML1/ETO and TEL/AML1 during normal and abnormal hematopoietic cell differentiation using the M-CSF receptor and blk as myeloid and Beta cell specific target genes, respectively.
The specific aims are 1) To analyze the mechanism of the synergy between AML1 and PU.1, 2) To study the role of AML1 fusion proteins in hematopoietic gene expression, 3) To study the effect of AML1-ETO on myeloid cell proliferation and differentiation by generating a murine AML1-ETO knock-in model.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA072009-04
Application #
6353497
Study Section
Project Start
2000-09-18
Project End
2001-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$348,824
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
Arinobu, Yojiro; Mizuno, Shin-ichi; Chong, Yong et al. (2007) Reciprocal activation of GATA-1 and PU.1 marks initial specification of hematopoietic stem cells into myeloerythroid and myelolymphoid lineages. Cell Stem Cell 1:416-27
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
Ross, Sarah E; Radomska, Hanna S; Wu, Bo et al. (2004) Phosphorylation of C/EBPalpha inhibits granulopoiesis. Mol Cell Biol 24:675-86
Shigematsu, Hirokazu; Reizis, Boris; Iwasaki, Hiromi et al. (2004) Plasmacytoid dendritic cells activate lymphoid-specific genetic programs irrespective of their cellular origin. Immunity 21:43-53

Showing the most recent 10 out of 52 publications