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

Masato Sasaki, Christiane B. Knobbe, Joshua C. Munger, Evan F. Lind, Dirk Brenner, Anne Brüstle, Isaac S. Harris, Roxanne Holmes, Andrew Wakeham, Jillian Haight, Annick You-Ten, Wanda Y. Li, Stefanie Schalm, Shinsan M. Su, Carl Virtanen, Guido Reifenberger, Pamela S. Ohashi, Dwayne L. Barber, Maria E. Figueroa, Ari MelnickJuan Carlos Zúñiga-Pflücker, Tak W. Mak

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323 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)656-659
Number of pages4
JournalNature
Volume488
Issue number7413
DOIs
StatePublished - Aug 30 2012

ASJC Scopus subject areas

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    Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E. F., Brenner, D., Brüstle, A., Harris, I. S., Holmes, R., Wakeham, A., Haight, J., You-Ten, A., Li, W. Y., Schalm, S., Su, S. M., Virtanen, C., Reifenberger, G., Ohashi, P. S., Barber, D. L., Figueroa, M. E., ... Mak, T. W. (2012). IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature, 488(7413), 656-659. https://doi.org/10.1038/nature11323