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A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders

Leukemia volume 25, pages 184–186 (2011)Cite this article

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Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are tricarboxylic acid cycle enzymes that catalyze conversion of isocitrate to α-ketoglutarate, operating in the cytosol and mitochondria, respectively. Recently, Parsons et al.1 described that IDH1 is mutated in 12% of glioblastomas, followed by the Yan et al.'s2 report showing a high frequency (80%) of IDH1 mutations at the R132 residue and less frequent IDH2 mutations at the R172 residue in grade II–III gliomas and secondary glioblastomas. IDH1 and IDH2 were shown to be also mutated in 7.7–9.9% and 15.4% of acute myeloid leukemia (AML) cases, respectively, especially those having normal karyotypes. More recently, both gene mutations were found in other myeloid neoplasms, including myeloproliferative neoplasms and myelodysplastic syndrome (MDS), and were associated with a high rate of MDS–AML transformation and poor prognosis.3, 4, 5 In hematopoietic neoplasms, all reported IDH1 mutations involved the R132 residue, while IDH2 mutations involve either the R172 or the R140 residue.

These mutations are thought to result in loss-of-function of these enzymes and prevent α-ketoglutarate production from isocitrate in a dominant-negative manner, which in turn leads to activation of the HIF-1α pathway.6 On the other hand, Dang et al.7 and Ward et al. demonstrated that mutant IDH1 and IDH2 also showed gain-of-function that promotes production of 2-hydroxyglutarate (2HG) from α-ketoglutarate, which is thought to be oncogenic. However, the relative contribution of loss-of-function and gain-of-function to oncogenesis is still unclear.

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Acknowledgements

This work was supported by a Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan (22140501) and from the Ministry of Education, Culture, Sports, Science and Technology, and NIH R01 CA026038-31.

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Authors and Affiliations

  1. Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    K Yoshida, M Sanada, M Kato, R Kawahata, A Matsubara & S Ogawa

  2. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    M Kato & J Takita

  3. Cell Therapy and Transplantation Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    J Takita

  4. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan

    L-Y Shih

  5. Division of Hematology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Kanagawa, Japan

    H Mori

  6. Department of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    H P Koeffler

  7. National University of Singapore, Cancer Institute of Singapore, Singapore, Singapore

    H P Koeffler

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  1. K Yoshida
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Correspondence to S Ogawa.

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Yoshida, K., Sanada, M., Kato, M. et al. A nonsense mutation of IDH1 in myelodysplastic syndromes and related disorders. Leukemia 25, 184–186 (2011). https://doi.org/10.1038/leu.2010.241

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