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Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice

Leukemia volume 28, pages 1343–1346 (2014)Cite this article

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Monoallelic point mutations in isocitrate dehydrogenase (IDH) define distinct subsets of lower-grade glioma and secondary glioblastoma, chondrosarcoma, intrahepatic cholangiocarcinomas and hematological malignancies. IDH is a metabolic enzyme that interconverts isocitrate and α-ketoglutarate (αKG), but cancer-associated point mutations in IDH confer a new or neomorphic activity that allows reduction of αKG to the oncometabolite R-2-hydroxyglutarate (2-HG).1 As a consequence, IDH-mutated cancers display increased intracellular 2-HG concentrations of 10- to 100-fold. In patients suffering from acute myeloid leukemias (AML), 2-HG level in serum is a predictor of the presence of IDH mutations and patient outcome.2, 3, 4 Although the precise oncogenic consequences of IDH mutations remain unclear, high levels of 2-HG have been shown to inhibit αKG-dependent dioxygenases, including the EglN prolyl-4-hydroxylases that regulate the activity of the hypoxia-responsive HIF transcription factor as well as the JmjC domain-containing histone demethylases and TET methylcytosine hydroxylases that have critical roles in epigenetic gene regulation (reviewed in Losman et al.5). Mutations of IDH and TET2 are mutually exclusive in AML suggesting that they may act along the same pathway.6 In human cancers, IDH mutants expression associates with hypermethylation of CpG loci and in vitro and in vivo modeling of IDH mutations results in histone H3 and H4 methylation modifications and DNA hypermethylation as well as block in cellular differentiation7 (and reviewed in Losman et al.5). Specific pharmacological inhibition of IDH mutants results in decrease of 2-HG levels and release of the differentiation block.8, 9, 10

Our data establish that IDH2R140Q is sufficient to initiate hematological malignancies from myeloid and lymphoid origin. In keeping with recent reports on IDH1R132H and IDH2R140Q KI mice models,11, 12, 13 the incomplete penetrance and long latency observed in our engrafted mice cohort confirm that additional mutations are required for complete transformation of hematopoietic cells and full-blown neoplasia. Genome-wide analysis of myeloid and lymphoid proliferations should help to identify the cooperating genetic alterations promoting neoplasia. The reasons for the difference between our BMT model and the KI model developed by Chen et al.12 in terms of type of malignancy and kinetics of disease development are unexplained at present but could be related to a difference in expression levels of the mutant. Indeed, it has been reported that IDH1R132H-mediated promotion of growth factor independence in the TF-1 cell line relies on 2-HG level.9 It will be critical to understand the relationship between IDH2R140Q activity, 2-HG levels and disease state in order to assess the clinical benefit of inhibition of IDH2R140Q-mediated 2-HG production by small molecules10 for patients suffering from myeloid and T-lymphoid neoplasms associated with mutant IDH2.

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Acknowledgements

We thank Jacques Bosq for thoughtful discussions, Philippe Rameau (PFIC, Institut Gustave Roussy, Villejuif, France) for cell-sorting cytometry, mice facility staff (Institut Gustave Roussy, Villejuif, France) and Audrey Joffrain for technical assistance. This work was supported by grants from INSERM, the Institut National du Cancer (INCa), the Cancéropôle Ile de France and the Association Laurette Fugain. MD is funded by a fellowship from the INCa (INCa-DGOS_5733).

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U985, Institut Gustave Roussy, Villejuif, France

    E Mylonas, M David, C Quivoron, O A Bernard, S DeBotton & V Penard-Lacronique

  2. Université Paris Sud-11, Orsay, France

    E Mylonas, M David, C Quivoron, O A Bernard, S DeBotton & V Penard-Lacronique

  3. Biochimie métabolique, Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Necker-Enfants Malades, Paris, France

    M Janin & C Ottolenghi

  4. INSERM U747, Université Paris Descartes, Paris, France

    M Janin & C Ottolenghi

  5. Plateforme d’évaluation préclinique, Institut Gustave Roussy, Villejuif, France

    O Bawa & P Opolon

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  1. E Mylonas
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Correspondence to V Penard-Lacronique.

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Author contributions

EM, OAB, CO, SDB and VPL designed research, analyzed data and wrote the manuscript. MJ performed the dosage of 2-HG. OB and PO carried out the histological analysis. MD and CQ performed the measure of 5mC and 5hmC content. All the authors read and approved the manuscript.

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Mylonas, E., Janin, M., Bawa, O. et al. Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice. Leukemia 28, 1343–1346 (2014). https://doi.org/10.1038/leu.2014.18

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