Mutant forms of isocitrate dehydrogenase (IDH) have been identified in 20% of AML. The goal of this project is to better understand the effects of mutant IDH on chromatin, and to develop novel therapies for IDH-mutant AML. Mutant forms of IDH1/2 gain a neomorphic function, producing 2-hydroxyglutarate (2HG) instead of the normal metabolite ?KG. 2HG inhibition of TET2, which mediates DNA hydroxymethylation, is a major mechanism of transformation by mutant IDH. However, 2HG also inhibits JmjC domain containing histone demethylases. Whether inhibition of JmjC demethylases and altered histone methylation contributes to leukemogenesis is currently not known. This project investigates the role of histone 3 lysine 79 methylation (H3K79me) in mutant-IDH mediated leukemogenesis. H3K79 methylation is increased in response to expression of mutant IDH, or exogenous exposure to 2HG, suggesting the existence of an H3K79 demethylase that is inhibited by 2HG. H3K79 is methylated by DOT1L. A contribution of aberrant H3K79 methylation to IDH?mutant leukemogenesis is highly relevant as a pharmacologic inhibitor of DOT1L is currently in clinical trials. This project will investigate whether DOT1L is required in IDH-mediated leukemogenesis using a murine leukemia model (SA1) as well as detailed analysis of changes in chromatin and gene expression in patient samples (SA2). Finally, the project aims to identify a demethylase for H3K79 (SA3).

Public Health Relevance

In 2014 there were an estimated 18,000 new cases of acute myeloid leukemia (AML) resulting in over 10,000 deaths. 20% of AML carry mutations in a gene called IDH. Mutant IDH may causes leukemia by changing histone proteins that associate with the DNA, and medications that reverse these changes could help treat AML.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA201230-03
Application #
9460182
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Mufson, R Allan
Project Start
2017-05-01
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104