Abstract

TEL is a new member of the Ets family of transcription factors which contribute to the pathogenesis of a wide variety of human hematopoietic malignancies. TEL is particularly remarkable because different chromosomal translocations result in the aberrant expression of different domains of the protein: either the DNA-binding Ets rearranged genes in human leukemia, little is known about the function of the normal TEL protein. In particular, the function of the HLH domain, highly conserved among Ets proteins, is entirely unknown. Our preliminary work, however, suggests that the TEL HLH domain encode a previously unrecognized self-association motif. Given the important role of TEL in hematopoietic malignancy, it is likely that TEL also plays a role in normal hematopoiesis. The overall goal of this proposal, therefore, is to take a first step toward the characterization of the biologic functions of the normal TEL protein, with an eye toward using these insights to understand the pathogenesis of TEL-associated leukemia.
The Specific Aims of this proposal are: To characterize TEL DNA-binding and trans-activation properties To characterize TEL protein-protein interactions and phosphorylation To examine the role of TEL in hematopoietic development and neoplasia in vivo It is anticipated that the elucidation of TEL structure/function relationships will promote a better understanding of both the mechanism of TEL-mediated transformation and the role of Ets proteins in hematopoiesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA072009-05
Application #
6472779
Study Section
Project Start
2001-07-06
Project End
2003-06-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
5
Fiscal Year
2001
Total Cost
$279,549
Indirect Cost

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

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