title: IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics.
abstract: Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas and cytogenetically normal acute myeloid leukaemias (AML). These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG). It remains unclear how IDH1 and IDH2 mutations modify myeloid cell development and promote leukaemogenesis. Here we report the characterization of conditional knock-in (KI) mice in which the most common IDH1 mutation, IDH1(R132H), is inserted into the endogenous murine Idh1 locus and is expressed in all haematopoietic cells (Vav-KI mice) or specifically in cells of the myeloid lineage (LysM-KI mice). These mutants show increased numbers of early haematopoietic progenitors and develop splenomegaly and anaemia with extramedullary haematopoiesis, suggesting a dysfunctional bone marrow niche. Furthermore, LysM-KI cells have hypermethylated histones and changes to DNA methylation similar to those observed in human IDH1- or IDH2-mutant AML. To our knowledge, our study is the first to describe the generation and characterization of conditional IDH1(R132H)-KI mice, and also the first report to demonstrate the induction of a leukaemic DNA methylation signature in a mouse model. Our report thus sheds light on the mechanistic links between IDH1 mutation and human AML.
authors: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors: Masato
authors: M
authors: Sasaki
authors: Christiane B
authors: CB
authors: Knobbe
authors: Joshua C
authors: JC
authors: Munger
authors: Evan F
authors: EF
authors: Lind
authors: Dirk
authors: D
authors: Brenner
authors: Anne
authors: A
authors: Brüstle
authors: Isaac S
authors: IS
authors: Harris
authors: Roxanne
authors: R
authors: Holmes
authors: Andrew
authors: A
authors: Wakeham
authors: Jillian
authors: J
authors: Haight
authors: Annick
authors: A
authors: You-Ten
authors: Wanda Y
authors: WY
authors: Li
authors: Stefanie
authors: S
authors: Schalm
authors: Shinsan M
authors: SM
authors: Su
authors: Carl
authors: C
authors: Virtanen
authors: Guido
authors: G
authors: Reifenberger
authors: Pamela S
authors: PS
authors: Ohashi
authors: Dwayne L
authors: DL
authors: Barber
authors: Maria E
authors: ME
authors: Figueroa
authors: Ari
authors: A
authors: Melnick
authors: Juan-Carlos
authors: JC
authors: Zúñiga-Pflücker
authors: Tak W
authors: TW
authors: Mak
mesh_terms: D000375:Aging; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D019070:Cell Lineage; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D055879:Gene Knock-In Techniques; D005910:Glioma / Q000473:pathology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D013154:Spleen / Q000473:pathology
chemical_list: D006657:Histones; D050505:Mutant Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human