IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics

Abstract

Mutations in isocitrate dehydrogenases IDH1 and IDH2 are common in human gliomas and acute myeloid leukaemias; here, mice that carry the IDH1(R132H) mutation are described, in a new model that should help in investigating the links between mutant IDH1 and leukaemia. Mutations in the IDH1 and IDH2 genes, which encode isocitrate dehydrogenases, are frequently found in human glioblastomas and acute myeloid leukaemias. These mutations drive the synthesis of the metabolite R-2-hydroxyglutarate (2HG), which inhibits enzymes that regulate levels of DNA and histone methylation. Here, Tak Mak and colleagues characterize conditional knock-in mice of the most common IDH1 mutation, IDH1–R132H, expressed in haematopoietic cells. The mutant mice have increased numbers of early haematopoietic progenitors and develop splenomegaly, anaemia and extramedullary haematopoiesis. Furthermore, cells exhibit changes in patterns of DNA and histone methylation that are similar to those observed in human IDH1/2-mutant acute myeloid leukaemias. This mouse model should be useful for the study of mechanistic links between mutant IDH1 and leukaemia. Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas1 and cytogenetically normal acute myeloid leukaemias (AML)2. These alterations are gain-of-function mutations in that they drive the synthesis of the ‘oncometabolite’ R-2-hydroxyglutarate (2HG)3. 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.