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Molecular targets for therapy

Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate

Leukemia volume 30, pages 1708–1715 (2016)Cite this article

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Abstract

Canonical mutations in IDH1 and IDH2 produce high levels of the R-enantiomer of 2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of α-ketoglutarate (αKG)-dependent enzymes and a putative oncometabolite. Mutant IDH1 collaborates with HoxA9 to induce monocytic leukemia in vivo. We used two mouse models and a patient-derived acute myeloid leukemia xenotransplantation (PDX) model to evaluate the in vivo transforming potential of R-2HG, S-2HG and αKG independent of the mutant IDH1 protein. We show that R-2HG, but not S-2HG or αKG, is an oncometabolite in vivo that does not require the mutant IDH1 protein to induce hyperleukocytosis and to accelerate the onset of murine and human leukemia. Thus, circulating R-2HG acts in a paracrine manner and can drive the expansion of many different leukemic and preleukemic clones that may express wild-type IDH1, and therefore can be a driver of clonal evolution and diversity. In addition, we show that the mutant IDH1 protein is a stronger oncogene than R-2HG alone when comparable intracellular R-2HG levels are achieved. We therefore propose R-2HG-independent oncogenic functions of mutant IDH1 that may need to be targeted in addition to R-2HG production to exploit the full therapeutic potential of IDH1 inhibition.

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Acknowledgements

We acknowledge assistance of the Cell Sorting Core Facility of Hannover Medical School supported, in part, by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft. We thank the staff of the Central Animal Facility of Hannover Medical School, Vishwas Sharma, Razif Gabdoulline, Michael Morgan, Silke Glowotz, Nicole Ernst and Martin Wichmann for their support on this project. We would also like to thank Dr Florian Kuchenbauer for providing the MLL-AF9 construct. This study was supported by an ERC grant under the European Union’s Horizon 2020 research and innovation program (No. 638035), by Grants 110284, 110287, 110292 and 111267 from Deutsche Krebshilfe; Grant DJCLS R13/14 from the Deutsche José Carreras Leukämie-Stiftung eV; the German Federal Ministry of Education and Research Grant 01EO0802 (IFB-Tx); DFG Grant HE 5240/5-1 and HE 5240/6-1; grants from Dieter-Schlag Stiftung, and a HiLF grant from Hannover Medical School awarded (to AC).

Author contributions

AC and MH designed the research; AC, MMAC, NJ, ASh, RGo, ASc, KG, RS, ES, EJ, CR, CM, RGe and GG performed the research; FT, AG and MH contributed patient samples and clinical data; AC, MMAC, ASc, CR, RGe and MH analyzed the data. AC and MH wrote the manuscript.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    A Chaturvedi, M M Araujo Cruz, N Jyotsana, A Sharma, R Goparaju, K Görlich, R Schottmann, A Ganser, F Thol & M Heuser

  2. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany

    A Schwarzer

  3. Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

    E A Struys & E E Jansen

  4. Department of Hematology and Oncology, University of Halle, Halle, Germany

    C Rohde & C Müller-Tidow

  5. Genome Analytics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany

    R Geffers

  6. Institute of Human Genetics, Hannover Medical School, Hannover, Germany

    G Göhring

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  1. A Chaturvedi
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Correspondence to M Heuser.

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Chaturvedi, A., Araujo Cruz, M., Jyotsana, N. et al. Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia 30, 1708–1715 (2016). https://doi.org/10.1038/leu.2016.71

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