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- Title
IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics.
- Authors
Sasaki, Masato; Knobbe, Christiane B.; Munger, Joshua C.; Lind, Evan F.; Brenner, Dirk; Brüstle, Anne; Harris, Isaac S.; Holmes, Roxanne; Wakeham, Andrew; Haight, Jillian; You-Ten, Annick; Li, Wanda Y.; Schalm, Stefanie; Su, Shinsan M.; Virtanen, Carl; Reifenberger, Guido; Ohashi, Pamela S.; Barber, Dwayne L.; Figueroa, Maria E.; Melnick, Ari
- 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.
- Subjects
GENETIC code; GENETIC mutation; HEMATOPOIETIC stem cells; PROGENITOR cells; EPIGENETICS; LABORATORY mice
- Publication
Nature, 2012, Vol 488, Issue 7413, p656
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature11323