The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development.

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State: Public
Version: Final published version
Serval ID
serval:BIB_7CE6633EE2A5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Lemonnier F., Cairns R.A., Inoue S., Li W.Y., Dupuy A., Broutin S., Martin N., Fataccioli V., Pelletier R., Wakeham A., Snow B.E., de Leval L., Pujals A., Haioun C., Paci A., Tobin E.R., Narayanaswamy R., Yen K., Jin S., Gaulard P., Mak T.W.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
27/12/2016
Peer-reviewed
Oui
Volume
113
Number
52
Pages
15084-15089
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease.

Keywords
Animals, Biomarkers, Tumor, Flow Cytometry, Gene Expression Regulation, Neoplastic, Genotype, Glutarates/metabolism, Humans, Isocitrate Dehydrogenase/genetics, Isocitrate Dehydrogenase/metabolism, Leukemia, Myeloid, Acute/genetics, Leukemia, Myeloid, Acute/metabolism, Lymphocytes/metabolism, Lymphoma, T-Cell/immunology, Lymphoma, T-Cell/metabolism, Mice, Mice, Knockout, Mutation, 2-hydroxyglutarate, AITL, T cell, isocitrate dehydrogenase, lymphoma
Pubmed
Web of science
Open Access
Yes
Create date
14/12/2016 16:24
Last modification date
20/08/2019 14:38
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