IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics.
Sasaki, Masato 1,10,,*; Knobbe, Christiane B. 1,2,10,,*; Munger, Joshua C. 3; Lind, Evan F. 1; Brenner, Dirk 1; Brustle, Anne 1; Harris, Isaac S. 1,4; Holmes, Roxanne 5; Wakeham, Andrew 1; Haight, Jillian 1; You-Ten, Annick 1; Li, Wanda Y. 1; Schalm, Stefanie 9; Su, Shinsan M. 9; Virtanen, Carl 6; Reifenberger, Guido 2; Ohashi, Pamela S. 1; Barber, Dwayne L. 4; Figueroa, Maria E. 7; Melnick, Ari 8; Zuniga-Pflucker, Juan-Carlos 5; Mk, Tk W. 1,4
[Letter]
Nature.
488(7413):656-659, August 30, 2012.
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: Mutations in the IDH1 and IDH2 genes encoding isocitrate dehydrogenases are frequently found in human glioblastomas 1 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.
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