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Acute myeloid leukemia

Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms

Abstract

Mutations in isocitrate dehydrogenase 1/2 (IDH1/2MT) are drivers of a variety of myeloid neoplasms. As they yield the same oncometabolite, D-2-hydroxyglutarate, they are often treated as equivalent, and pooled. We studied the validity of this approach and found IDH1/2 mutations in 179 of 2119 myeloid neoplasms (8%). Cross-sectionally, the frequencies of these mutations increased from lower- to higher risk disease, thus suggesting a role in clinical progression. Variant allelic frequencies indicated that IDH1MT and IDH2MT are ancestral in up to 14/74 (19%) vs 34/99 (34%; P=0.027) of cases, respectively, illustrating the pathogenic role of these lesions in myeloid neoplasms. IDH1/2MT was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1MT cases were associated with a worse prognosis than subclonal IDH1MT cases, whereas the position of IDH2MT within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1MT cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2MT cases. Our data demonstrate important clinical and biological differences between IDH1MT and IDH2MT myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2MT inhibitors of IDH1/2MT patients.

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Acknowledgements

This work was supported by National Institutes of Health (Bethesda, MD, USA; NIH) grants RO1HL-082983 (JPM), U54 RR019391 (JPM), K24 HL-077522 (JPM), a grant from the AA & MDS International Foundation (Rockville, MD, USA; JPM), the Robert Duggan Charitable Fund (Cleveland, OH, USA; JPM) and Scott Hamilton CARES grant (Cleveland, OH, USA; HM), a grant from the AA & MDS International Foundation (HM) and Grant-in-Aids from the Ministry of Health, Labor and Welfare of Japan and KAKENHI (23249052, 22134006 and 21790907) (Tokyo, Japan; SO), project for development of innovative research on cancer therapies (p-direct) (Tokyo, Japan; SO), the Japan Society for the Promotion of Science (JSPS) through the ‘Funding Program for World-Leading Innovative R&D on Science and Technology’, initiated by the Council for Science and Technology Policy (CSTP) (Tokyo, Japan; SO), the Dutch Cancer Society (KWF; UVA 2014-6839) (CJFvN, RJM and FEB), an AMC PhD Scholarship (RJM), the American Society of Hematology Research Training award for fellows and a Damon Runyon Postdoctoral Fellowship (DRG 117-15, ADV), Grant-in-Aids from the Ministry of Health, Labor and Welfare of Japan and KAKENHI (23249052, 22134006, 24221011 and 21790907; TH), by the Industrial Technology Research Grant Program from NEDO (08C46598a; TH), by Project for Development of Innovative Research on Cancer Therapeutics (P-Direct; TH) and by the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST, TH) and Edward P Evans AA/MDS foundation (MAS). The results presented here are partly based upon the data generated by The Cancer Genome Atlas pilot project established by the NCI and NHGRI.

Author contributions

RJM, ST, CJFvN, HC, MAS, SO, TH, JPM designed research; RJM, ST, HM, BPa, BPr, MC, CH, NH, MM, TA, YS, KC and HT performed research; RJM, ST, HM and TR analyzed data; all authors wrote and reviewed the paper. RJM and ST contributed equally to this study.

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Correspondence to J P Maciejewski.

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Molenaar, R., Thota, S., Nagata, Y. et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 29, 2134–2142 (2015). https://doi.org/10.1038/leu.2015.91

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