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  • Cell Lineage  (1)
  • Hematopoiesis  (1)
  • Isocitrate Dehydrogenase/*genetics/*metabolism  (1)
  • Nature Publishing Group (NPG)  (1)
  • Nature Publishing Group (NPG)  (1)
  • 1
    Publication Date: 2012-07-06
    Description: 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.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sasaki, Masato -- Knobbe, Christiane B -- Munger, Joshua C -- Lind, Evan F -- Brenner, Dirk -- Brustle, 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 -- Zuniga-Pflucker, Juan-Carlos -- Mak, Tak W -- R01 AI081773/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2012 Aug 30;488(7413):656-9. doi: 10.1038/nature11323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: 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
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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