Knowledge of the mechanisms underlying the normal development of blood cells will lead to new understanding of the pathogenesis of acute leukemias. The long range goals are to further understanding of the mechanisms involved in leukemia, to develop new prognostic classifications based on molecular mechanisms, and then to develop more specific, less toxic therapies for leukemia (""""""""Transcription"""""""" therapies). The major hypotheses underlying this research program are that: (1) Acute-myelogenous leukemia (AML;) represents a block in hematopoietic cell differentiation; (2) Hematopoietic cell differentiation is largely determined by lineage specific transcription factors; (3) Therefore, :abnormalities in these transcription factors (mutation, decreased expression, post-translational modifications, abnormal cellular localization) are likely to play a major role in AML; (4) Detecting these abnormalities will lead to new classifications of AML and new prognostic indicators, much like those associated with specific chromosomal translocations; (S) These studies will lead to new strategies for treatment, either based on drug or gene therapy; and (6) These studies will form a paradigm for understanding and eventually developing specific therapies for other leukemias and cancers. Recent studies led to the identification of the transcription factor CCAAT Enhancer Binding Protein alpha (C/EBPa) as being absolutely critical for differentiation of normal myeloid blasts and has specific abnormalities in specific AML subtypes.
The specific aims are: (1) To demonstrate that mutant C/EBPa ; blocks differentiation in cell lines, primary bone marrow cells, and mouse models of human AML; (2) To further characterize the abnormalities in patients with AML and mutations in C/EBPa; and (3) To demonstrate that introduction of wild type C/EBPa can induce differentiation of leukemic cells as proof of aboutprinciple for development of future therapies. These studies will provide information concerning the pathogenesis and treatment of AML, as well as develop techniques applicable to other human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA088046-04
Application #
6647180
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Mufson, R Allan
Project Start
2000-09-20
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$298,008
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Yin, Hong; Radomska, Hanna S; Tenen, Daniel G et al. (2006) Down regulation of PSA by C/EBPalpha is associated with loss of AR expression and inhibition of PSA promoter activity in the LNCaP cell line. BMC Cancer 6:158
Hess, Angela R; Hendrix, Mary J C (2006) Focal adhesion kinase signaling and the aggressive melanoma phenotype. Cell Cycle 5:478-80
Wagner, Katharina; Zhang, Pu; Rosenbauer, Frank et al. (2006) Absence of the transcription factor CCAAT enhancer binding protein alpha results in loss of myeloid identity in bcr/abl-induced malignancy. Proc Natl Acad Sci U S A 103:6338-43
Hess, Angela R; Seftor, Elisabeth A; Gruman, Lynn M et al. (2006) VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: implications for vasculogenic mimicry. Cancer Biol Ther 5:228-33
Hess, Angela R; Postovit, Lynne-Marie; Margaryan, Naira V et al. (2005) Focal adhesion kinase promotes the aggressive melanoma phenotype. Cancer Res 65:9851-60
Rosenbauer, Frank; Koschmieder, Steffen; Steidl, Ulrich et al. (2005) Effect of transcription-factor concentrations on leukemic stem cells. Blood 106:1519-24
Schwieger, Maike; Lohler, Jurgen; Fischer, Meike et al. (2004) A dominant-negative mutant of C/EBPalpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Blood 103:2744-52
Truong, Bao-Tran H; Lee, Young-Jin; Lodie, Tracey A et al. (2003) CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101:1141-8
Halmos, Balazs; Huettner, Claudia S; Kocher, Olivier et al. (2002) Down-regulation and antiproliferative role of C/EBPalpha in lung cancer. Cancer Res 62:528-34