期刊
LEUKEMIA
卷 29, 期 11, 页码 2134-2142出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.91
关键词
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资金
- National Institutes of Health (Bethesda, MD, USA
- NIH) [RO1HL-082983, U54 RR019391, K24 HL-077522]
- AA & MDS International Foundation (Rockville, MD, USA)
- Robert Duggan Charitable Fund (Cleveland, OH, USA)
- Scott Hamilton CARES grant (Cleveland, OH, USA)
- AA & MDS International Foundation
- Ministry of Health, Labor and Welfare of Japan (Tokyo, Japan) [23249052, 22134006, 21790907]
- project for development of innovative research on cancer therapies (p-direct) (Tokyo, Japan)
- Japan Society for the Promotion of Science (JSPS) through the 'Funding Program for World-Leading Innovative R&D on Science and Technology'
- Council for Science and Technology Policy (CSTP) (Tokyo, Japan)
- Dutch Cancer Society (KWF) [UVA 2014-6839]
- AMC PhD Scholarship
- American Society of Hematology Research Training award
- Damon Runyon Postdoctoral Fellowship [DRG 117-15]
- Ministry of Health, Labor and Welfare of Japan [23249052, 22134006, 21790907, 24221011]
- Industrial Technology Research Grant Program from NEDO [08C46598a]
- Project for Development of Innovative Research on Cancer Therapeutics
- Funding Program for World-Leading Innovative R&D on Science and Technology
- Edward P Evans AA/MDS foundation
- Grants-in-Aid for Scientific Research [22134006, 23249052, 21790907] Funding Source: KAKEN
Mutations in isocitrate dehydrogenase 1/2 (IDH1/2(MT)) 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 IDH1(MT) and IDH2(MT) 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. IDH1/2(MT) was associated with poor overall survival, particularly in lower risk myelodysplastic syndromes. Ancestral IDH1(MT) cases were associated with a worse prognosis than subclonal IDH1(MT) cases, whereas the position of IDH2(MT) within clonal hierarchy did not impact survival. This may relate to distinct mutational spectra with more DNMT3A and NPM1 mutations associated with IDH1(MT) cases, and more ASXL1, SRSF2, RUNX1, STAG2 mutations associated with IDH2(MT) cases. Our data demonstrate important clinical and biological differences between IDH1(MT) and IDH2(MT) myeloid neoplasms. These mutations should be considered separately as their differences could have implications for diagnosis, prognosis and treatment with IDH1/2(MT) inhibitors of IDH1/2(MT) patients.
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