IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics
Open accessAbstract
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.
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Knock-in of mutant IDH1 allele into normal hematopoietic cells and chondrocytes in vivo triggers aberrant expansion of targeted cell lineages.
“Furthermore, a knock-in of a mutant IDH1 allele into normal hematopoietic cells and into chondrocytes in vivo triggers an aberrant expansion of targeted cell lineages (Hirata et al., 2015; Sasaki et al., 2012).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Sasaki et al., 2012
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- Authors
- 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., Melnick, A., Zúñiga-Pflücker, J.-C., & Mak, T. W.
- Affiliations
- University Health Network (CA)
- University of Rochester Medicine (US)
- University of Toronto (CA)
- Agios Pharmaceuticals (United States) (US)
- Heinrich Heine University Düsseldorf (DE)
- Cornell University (US)
- Corresponding author
- Mak, Tak W.
- ORCID
- Venue
- Nature
- Published
- 2012-07-04
- Volume
- 488
- Issue
- 7413
- Pages
- 656-659
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4005896
- OpenAlex
- W2035409103
- Cited by
- 513
- References
- 34
- Citations by year
- 2026: 5 · 2025: 20 · 2024: 16 · 2023: 27 · 2022: 26 · 2021: 31 · 2020: 28 · 2019: 34 · 2018: 33 · 2017: 44 · 2016: 55 · 2015: 55 · 2014: 53 · 2013: 64 · 2012: 21
- FWCI
- 41.37
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute of Allergy and Infectious Diseases (R56AI081773, R01AI081773)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- IDH1 R132H mutation, isocitrate dehydrogenase, 2-hydroxyglutarate, acute myeloid leukemia, hematopoietic progenitor cells, epigenetics, DNA methylation, histone methylation, conditional knock-in mice, extramedullary hematopoiesis, splenomegaly, anemia
- MeSH terms
- Aging, Animals, Bone Marrow, Disease Models, Animal, Female, Glioma, Hematopoiesis, Hematopoietic Stem Cells, Histones, Humans, Isocitrate Dehydrogenase, Male, Mutation, Spleen, Leukemia, Myeloid, Acute, CpG Islands, Cell Lineage, DNA Methylation, Myeloid Cells, Epigenesis, Genetic, Mutant Proteins, Mice, Gene Knock-In Techniques
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