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: 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 Melnick, Juan-Carlos Zúñiga-Pflücker, Tak W Mak
• Journal: Nature (Nature) Vol. 488 Issue 7413 Pg. 656-9 (Aug 30 2012) ISSN: 1476-4687 [Electronic] England
• PMID: 22763442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histones
• Mutant Proteins
• Isocitrate Dehydrogenase
• IDH1 protein, human

Topics

• Aging
• Animals
• Bone Marrow (pathology)
• Cell Lineage
• CpG Islands (genetics)
• DNA Methylation
• Disease Models, Animal
• Epigenesis, Genetic (genetics)
• Female
• Gene Knock-In Techniques
• Glioma (pathology)
• Hematopoiesis
• Hematopoietic Stem Cells (cytology, metabolism)
• Histones (metabolism)
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Leukemia, Myeloid, Acute (genetics)
• Male
• Mice
• Mutant Proteins (genetics, metabolism)
• Mutation (genetics)
• Myeloid Cells (cytology, metabolism)
• Spleen (pathology)