期刊
NATURE
卷 488, 期 7413, 页码 656-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nature11323
关键词
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资金
- Feodor-Lynen Postdoctoral Research Fellowship from the Alexander-von-Humboldt-Foundation, Germany
- German Research Foundation (DFG)
- National Institute of Health [NIH R01AI081773]
- Damon Runyon Cancer Research Foundation [DRR-09-10]
- Leukemia & Lymphoma Society
- Doris Duke Clinical Scientist Development Award
- LLS SCOR grant [7132-08]
- Burroughs Wellcome Clinical Translational Scientist Award
- Starr Cancer Consortium [I4-A442]
- Canada Research Chair in Developmental Immunology
- Canadian Institutes of Health Research (CIHR)
- Ontario Ministry of Health and Long Term Care
- Terry Fox Foundation
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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