Acute myeloid leukemia (AML) is marked by a profound block in the ability of the malignant cells to differentiate. Although progress has been made in understanding how the mutations in AML contribute to increasing the proliferation and survival of the leukemic cells, relatively little is known about how the cells'ability to differeniate is inhibited. Most of the recent research on this issue has delineated a role for oncogenes in maintaining the expression of genes required to maintain a stem cell phenotype and many of these undoubtedly contribute to AML pathogenesis. The discovery of recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) that result in a gain-of-function ability to produce the metabolite 2-hydroxyglutarate (2HG) has suggested an additional mechanism by which normal differentiation can be blocked. We have found that 2HG can act as a competitive inhibitor of both the TET family of DNA hydroxylases and the Jumonji family of histone demethylases. As a consequence, IDH-mutant cells display enhanced DNA and histone methylation. This enhanced methylation correlated with the inability of leukemic cells to activate lineage-specific genes involved in cellular differentiation. Despite these correlations, there remain differences in the prognostic implications of IDH1 and IDH2 mutations in leukemia and uncertainty concerning the role 2HG plays in their transforming properties. To address these issues we propose 3 Specific Aims: 1) Investigate the mechanistic basis for the differential implication of IDH1 R132 or IDH2 R172 versus IDH2 R140 mutations in leukemic prognosis;2) Compare the effects of IDH mutation versus TET2 mutation on histone methylation status and gene expression in AML;3) Determine if the manipulation of 2HG levels can suppress IDH-associated leukemia. Through our proposed studies we hope to broaden our understanding of the molecular regulation of hematopoietic differentiation, provide an explanation for the differences in the chromatin structure observed among AML cases, and develop new therapeutic approaches to AML.

Public Health Relevance

The discovery of mutations in enzymes which produce metabolites that can disrupt the epigenetic regulation of cell differentiation potentially opens up new therapeutic approaches to the treatment of AML. In this proposal, we will undertake proof-of-concept experiments to confirm the role of mutant isocitrate dehydrogenase (IDH) enzymes and their enzymatic production of 2-hydroxyglutarate (2HG) in the pathogenesis of acute myeloid leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168802-02
Application #
8634071
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$355,854
Indirect Cost
$154,579
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Venneti, Sriram; Santi, Mariarita; Felicella, Michelle Madden et al. (2014) A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol 128:743-53