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="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005896/" 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="http://www.ncbi.nlm.nih.gov/pubmed/22763442" 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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