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

François Lemonnier, Rob A. Cairns, Satoshi Inoue, Wanda Y. Li, Aurélie Dupuy, Sophie Broutin, Nadine Martin, Virginie Fataccioli, Romain Pelletier, Andrew Wakeham, Bryan E. Snow, Laurence De Leval, Anais Pujals, Corinne Haioun, Angelo Paci, Erica R. Tobin, Rohini Narayanaswamy, Katherine Yen, Shengfang Jin, Philippe GaulardTak W. Mak

Research output: Contribution to journalArticlepeer-review

88 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)15084-15089
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number52
DOIs
Publication statusPublished - 2016 Dec 27
Externally publishedYes

Keywords

  • 2-hydroxyglutarate
  • AITL
  • Isocitrate dehydrogenase
  • Lymphoma
  • T cell

ASJC Scopus subject areas

  • General

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