title: The IDH2 R172K mutation associated with angioimmunoblastic T-cell lymphoma produces 2HG in T cells and impacts lymphoid development.
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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.|Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
authors.forename: François
authors.initials: F
authors.lastname: Lemonnier
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dupuy
authors.affiliation: Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Broutin
authors.affiliation: Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.affiliation: Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Fataccioli
authors.affiliation: Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Pelletier
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Snow
authors.affiliation: Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: de Leval
authors.affiliation: Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
authors.forename: Anais
authors.initials: A
authors.lastname: Pujals
authors.affiliation: Unité Hémopathies Lymphoïdes, Groupe Henri-Mondor Albert-Chenevier, Assistance Publique-Hôpitaux de Paris, 94010, Créteil, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.
authors.forename: Angelo
authors.initials: A
authors.lastname: Paci
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA 02139.
authors.forename: Erica R
authors.initials: ER
authors.lastname: Tobin
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA 02139.
authors.forename: Rohini
authors.initials: R
authors.lastname: Narayanaswamy
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA 02139.
authors.forename: Katherine
authors.initials: K
authors.lastname: Yen
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA 02139; tmak@uhnresearch.ca philippe.gaulard@aphp.fr shengfang.jin@agios.com.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Inserm U955, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France; tmak@uhnresearch.ca philippe.gaulard@aphp.fr shengfang.jin@agios.com.|Département de Pathologie, Groupe Henri-Mondor Albert-Chenevier, Assistance Publique-Hôpitaux de Paris, 94010, Créteil, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada; tmak@uhnresearch.ca philippe.gaulard@aphp.fr shengfang.jin@agios.com.|Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation
chemical_list: D014408:Biomarkers, Tumor; D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: 2-hydroxyglutarate; AITL; T cell; isocitrate dehydrogenase; lymphoma