期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：52
页码：15084-15089
DOI：10.1073/pnas.1617929114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMutations in isocitrate dehydrogenase (IDH)1 and IDH2 contribute to malignant progression by producing the oncometabolite 2HG. In myeloid disorders, mutations at three positions in these genes are commonly observed, but in angioimmunoblastic T-cell lymphoma (AITL), IDH mutations are restricted to IDH2 arginine (R) 172. The complex microenvironment of AITL, where malignant T cells comprise a minority of the tumor, has made it difficult to evaluate the role of this mutation. Here, we provide clinical data showing that mutant IDH2 expression is restricted to malignant T cells and that 2HG may be a useful biomarker in AITL. In addition, using conditional knock-in mouse models, we find that only mutations at IDH2 R172 produce significant quantities of 2HG in lymphoid cells and alter lymphoid development. 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.
