title: Idh1 mutations contribute to the development of T-cell malignancies in genetically engineered mice.
abstract: Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant Idh1. We observed the development of a spontaneous T-cell acute lymphoblastic leukemia (T-ALL) in these animals. The disease was transplantable and maintained expression of mutant IDH1. Whole-exome sequencing revealed the presence of a spontaneous activating mutation in Notch1, one of the most common mutations in human T-ALL, suggesting Idh1 mutations may have the capacity to cooperate with Notch1 to drive T-ALL. To further investigate the Idh1 mutation as an oncogenic driver in the T-cell lineage, we crossed Idh1-KI mice with conditional Trp53 null mice, a well-characterized model of T-cell malignancy, and found that T-cell lymphomagenesis was accelerated in mice bearing both mutations. Because both IDH1 and p53 are known to affect cellular metabolism, we compared the requirements for glucose and glutamine in cells derived from these tumors and found that cells bearing the Idh1 mutation have an increased dependence on both glucose and glutamine. These data suggest that mutant IDH1 contributes to malignancy in the T-cell lineage and may alter the metabolic profile of malignant T cells.
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: Zhenyue
authors.initials: Z
authors.lastname: Hao
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: Department of Biology, York University, Toronto, ON, M3J 1P3, Canada;
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
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 and Département de Pathologie, Groupe Henri-Mondor Albert-Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, 94000 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: 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: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2C1, Canada;
authors.forename: Carmen
authors.initials: C
authors.lastname: Dominguez-Brauer
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: Jing
authors.initials: J
authors.lastname: Ye
authors.affiliation: Mbed Pathology, Toronto, Ontario, M5N 2G4, Canada;
authors.forename: Dana M
authors.initials: DM
authors.lastname: Larsen
authors.affiliation: Agios Pharmaceuticals, Cambridge, MA, 02139;
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Straley
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: Inserm U955, Université Paris Est and Département de Pathologie, Groupe Henri-Mondor Albert-Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, 94000 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; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada tmak@uhnresearch.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D059472:Exome; D016158:Genes, p53; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D051379:Mice; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D007521:Isocitrate Dehydrogenase
keywords: T-ALL; isocitrate dehydrogenase; lymphoma; p53