IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics

Masato Sasaki, Christiane B. Knobbe, Joshua C. Munger, Evan 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 & 2 others Juan Carlos Zúñiga-Pflücker, Tak W. Mak

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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.

Original languageEnglish (US)
Pages (from-to)656-659
Number of pages4
JournalNature
Volume488
Issue number7413
DOIs
StatePublished - Aug 30 2012
Externally publishedYes

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Epigenomics
Mutation
Acute Myeloid Leukemia
DNA Methylation
Extramedullary Hematopoiesis
Isocitrate Dehydrogenase
Splenomegaly
Cell Lineage
Myeloid Cells
Glioblastoma
Histones
Anemia
Bone Marrow
Genes

ASJC Scopus subject areas

  • General

Cite this

Sasaki, M., Knobbe, C. B., Munger, J. C., Lind, E., Brenner, D., Brüstle, A., ... Mak, T. W. (2012). IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature, 488(7413), 656-659. https://doi.org/10.1038/nature11323

IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. / Sasaki, Masato; Knobbe, Christiane B.; Munger, Joshua C.; Lind, Evan; Brenner, Dirk; Brüstle, 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; Zúñiga-Pflücker, Juan Carlos; Mak, Tak W.

In: Nature, Vol. 488, No. 7413, 30.08.2012, p. 656-659.

Research output: Contribution to journalArticle

Sasaki, M, Knobbe, CB, Munger, JC, Lind, E, Brenner, D, Brüstle, A, Harris, IS, Holmes, R, Wakeham, A, Haight, J, You-Ten, A, Li, WY, Schalm, S, Su, SM, Virtanen, C, Reifenberger, G, Ohashi, PS, Barber, DL, Figueroa, ME, Melnick, A, Zúñiga-Pflücker, JC & Mak, TW 2012, 'IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics', Nature, vol. 488, no. 7413, pp. 656-659. https://doi.org/10.1038/nature11323
Sasaki M, Knobbe CB, Munger JC, Lind E, Brenner D, Brüstle A et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature. 2012 Aug 30;488(7413):656-659. https://doi.org/10.1038/nature11323
Sasaki, Masato ; Knobbe, Christiane B. ; Munger, Joshua C. ; Lind, Evan ; Brenner, Dirk ; Brüstle, 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 ; Zúñiga-Pflücker, Juan Carlos ; Mak, Tak W. / IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. In: Nature. 2012 ; Vol. 488, No. 7413. pp. 656-659.
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AU - Brüstle, Anne

AU - Harris, Isaac S.

AU - Holmes, Roxanne

AU - Wakeham, Andrew

AU - Haight, Jillian

AU - You-Ten, Annick

AU - Li, Wanda Y.

AU - Schalm, Stefanie

AU - Su, Shinsan M.

AU - Virtanen, Carl

AU - Reifenberger, Guido

AU - Ohashi, Pamela S.

AU - Barber, Dwayne L.

AU - Figueroa, Maria E.

AU - Melnick, Ari

AU - Zúñiga-Pflücker, Juan Carlos

AU - Mak, Tak W.

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