The post-translational modification of the core histones plays a vital role in the regulation of cellular processes that involve access to chromosomal DNA and subsequent gene transcription. These processes are disregulated in a large proportion of cancers including the two most common types of adult leukemia, acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). To better understand the impact of these modifications on the development and progression of AML and CLL, we intend to develop assays for screening AML and CLL-specific patterns of histone modification and conduct a detailed molecular analysis to identify the specific histone isoforms present in different genetic subtypes of AML and CLL and their impact on patient outcome. Furthermore we will characterize the changes in the histone modification induced by HDAC inhibitors that correlate with induction of apoptosis and differentiation in vitro and in vivo in AML and CLL cells. These findings will then be applied to patient tumor cell samples obtained from subjects receiving the histone deacetylase inhibitor depsipeptide and potentially other histone deacetylase inhibitors used by our clinical group to predict early treatment outcome of this therapy. Thus, use of the techniques developed and validated in this proposal will allow basic scientists to understand specific post-translational changes observed in histone proteins and clinical-translational scientists to effectively predict outcome and apply therapies that modify these in patients with AML and CLL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107106-03
Application #
7115333
Study Section
Special Emphasis Panel (ZRG1-BECM (01))
Program Officer
Mufson, R Allan
Project Start
2004-09-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$229,930
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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