Abstract
Purpose
The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by the presence of somatically mutated hematopoietic stem cells (HSCs) that increase the risk of progression to secondary acute myeloid leukemia (sAML). Mutations in isocitrate dehydrogenase (IDHmut) are thought to correlate with the increased production of the oncogenic protein 2-hydroxyglutarate (2-HG) in AML. The aim of this study was to examine whether serum 2-HG has utility as a prognostic biomarker, and whether elevated 2-HG levels are predictive of IDH mutations in patients with MDS.
Methods
Genetic profiling was utilized to determine the genetic composition of a large cohort of MDS patients, including the presence or absence of IDH1 or IDH2 mutations (n = 281). Serum 2-HG levels were detected by liquid chromatography–tandem mass spectrometry.
Results
In the current study of MDS patients, elevated serum 2-HG levels were predictive of inferior overall- and leukemia-free survival irrespective of IPSS risk grouping. Higher serum 2-HG levels predicted the presence of IDH mutations. IDH2mut patients had a higher risk of leukemic transformation. The co-occurrence of DNMT3A or SRSF2 mutations was found to be increased in IDH2mut patients. IDH2 mutations were associated with significantly worse OS and LFS amongst patients with low-risk MDS by IPSS grouping.
Conclusions
The noted predictive value of serum 2-HG levels and IDH2 mutations on OS and LFS support the use of biomarkers and/or underlying cytogenetics in novel prognostic scoring systems for MDS.
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References
Ahmad F, Mohota R, Sanap S, Mandava S, Das BR (2014) Molecular evaluation of DNMT3A and IDH1/2 gene mutation: frequency, distribution pattern and associations with additional molecular markers in normal karyotype Indian acute myeloid leukemia patients. Asian Pac J Cancer Prev: APJCP 15:1247–1253
Bejar R et al (2011) Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364:2496–2506. https://doi.org/10.1056/NEJMoa1013343
Cazzola M, Malcovati L (2005) Myelodysplastic syndromes—coping with ineffective hematopoiesis. N Engl J Med 352:536–538. https://doi.org/10.1056/NEJMp048266
Chen C et al (2013) Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition. Genes Dev 27:1974–1985. https://doi.org/10.1101/gad.226613.113
Choi C et al (2012) 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18:624–629. https://doi.org/10.1038/nm.2682
Dang L et al (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744. https://doi.org/10.1038/nature08617
DiNardo CD et al (2013) Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute. Myeloid Leukemia Blood 121:4917–4924. https://doi.org/10.1182/blood-2013-03-493197
Ehrlich M (2009) DNA hypomethylation in cancer cells. Epigenomics 1:239–259. https://doi.org/10.2217/epi.09.33
Fathi AT et al (2012) Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and. Therapeutic Response Blood 120:4649–4652. https://doi.org/10.1182/blood-2012-06-438267
Figueroa ME et al (2010) Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18:553–567. https://doi.org/10.1016/j.ccr.2010.11.015
Graveley BR, Maniatis T (1998) Arginine/serine-rich domains of SR proteins can function as activators of pre-mRNA. Splicing Mol Cell 1:765–771
Green CL, Evans CM, Hills RK, Burnett AK, Linch DC, Gale RE (2010) The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/. ITD Status Blood 116:2779–2782. https://doi.org/10.1182/blood-2010-02-270926
Greenberg P et al (1997) International scoring system for evaluating prognosis in. Myelodysplast Syndr Blood 89:2079–2088
Greenberg PL et al (2012) Revised international prognostic scoring system for. Myelodysplast syndromes Blood 120:2454–2465. https://doi.org/10.1182/blood-2012-03-420489
Gross S et al (2010) Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med 207:339–344. https://doi.org/10.1084/jem.20092506
Jin J et al (2014) Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLoS One 9:e100206. https://doi.org/10.1371/journal.pone.0100206
Kats LM et al (2014) Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance. Cell Stem Cell 14:329–341. https://doi.org/10.1016/j.stem.2013.12.016
Kim E et al (2015) SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon. Recognition Cancer Cell 27:617–630. https://doi.org/10.1016/j.ccell.2015.04.006
Kosmider O et al (2010) Mutations of IDH1 and IDH2 genes in early and accelerated phases of myelodysplastic syndromes and MDS/myeloproliferative neoplasms. Leukemia 24:1094–1096. https://doi.org/10.1038/leu.2010.52
Kranendijk M, Struys EA, Salomons GS, Van der Knaap MS, Jakobs C (2012) Progress in understanding 2-hydroxyglutaric acidurias. J Inherit Metab Dis 35:571–587. https://doi.org/10.1007/s10545-012-9462-5
Ley TJ et al (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424–2433. https://doi.org/10.1056/NEJMoa1005143
Lin J et al (2012) IDH1 and IDH2 mutation analysis in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol 91:519–525. https://doi.org/10.1007/s00277-011-1352-7
Lin CC et al (2014a) IDH mutations are closely associated with mutations of DNMT3A, ASXL1 and SRSF2 in patients with myelodysplastic syndromes and are stable during disease evolution. Am J Hematol 89:137–144. https://doi.org/10.1002/ajh.23596
Lin TL et al (2014b) Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2. Mutat Haematol 99:28–36. https://doi.org/10.3324/haematol.2013.091249
Losman JA, Kaelin WG Jr (2013) What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27:836–852. https://doi.org/10.1101/gad.217406.113
Lu C et al (2013) Induction of sarcomas by mutant IDH. 2 Genes Dev 27:1986–1998. https://doi.org/10.1101/gad.226753.113
Makishima H et al (2017) Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet 49:204–212. https://doi.org/10.1038/ng.3742
Ogawara Y et al (2015) IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and Hypoxia pathways in acute myeloid. Leuk Cancer Res 75:2005–2016. https://doi.org/10.1158/0008-5472.can-14-2200
Patnaik MM et al (2012) Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277. Patients Leuk 26:101–105. https://doi.org/10.1038/leu.2011.298
Patnaik MM et al (2013) Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol 88:201–206. https://doi.org/10.1002/ajh.23373
Rakheja D, Mitui M, Boriack RL, DeBerardinis RJ (2011) Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors. Pediatr Blood Cancer 56:379–383. https://doi.org/10.1002/pbc.22697
Reitman ZJ, Yan H (2010) Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 102:932–941. https://doi.org/10.1093/jnci/djq187
Schaal TD, Maniatis T (1999) Multiple distinct splicing enhancers in the protein-coding sequences of a constitutively spliced pre-mRNA. Mol Cell Biol 19:261–273
Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31:27–36. https://doi.org/10.1093/carcin/bgp220
Smolkova K, Jezek P (2012) The role of mitochondrial NADPH-dependent isocitrate dehydrogenase in cancer cells. Int J Cell Biol 2012:273947 https://doi.org/10.1155/2012/273947
Steenweg ME et al (2010) An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study. Hum Mutat 31:380–390. https://doi.org/10.1002/humu.21197
Struys EA, Jansen EE, Verhoeven NM, Jakobs C (2004) Measurement of urinary D- and L-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-L-tartaric anhydride. Clin Chem 50:1391–1395. https://doi.org/10.1373/clinchem.2004.033399
Struys EA et al (2005) Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. Am J Hum Genet 76:358–360. https://doi.org/10.1086/427890
Tefferi A et al (2010) IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia. Polycythemia Vera Myelofibrosis Leuk 24:1302–1309. https://doi.org/10.1038/leu.2010.113
Thol F et al (2010) Prognostic impact of IDH2 mutations in cytogenetically normal acute. Myeloid Leuk Blood 116:614–616. https://doi.org/10.1182/blood-2010-03-272146
Wang F et al (2013a) Targeted inhibition of mutant IDH2 in leukemia cells induces cellular. Differentiation Sci 340:622–626. https://doi.org/10.1126/science.1234769
Wang JH et al (2013b) Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia. China Proc Natl Acad Sci USA 110:17017–17022. https://doi.org/10.1073/pnas.1315558110
Ward PS et al (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-. Hydroxyglutarate Cancer Cell 17:225–234. https://doi.org/10.1016/j.ccr.2010.01.020
Xu W et al (2011) Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent. Dioxygenases Cancer Cell 19:17–30. https://doi.org/10.1016/j.ccr.2010.12.014
Yan H et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. https://doi.org/10.1056/NEJMoa0808710
Yen K et al (2017) AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2. Mutat Cancer Discov 7:478–493. https://doi.org/10.1158/2159-8290.CD-16-1034
Zhao S et al (2009) Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1. Alpha Sci 324:261–265. https://doi.org/10.1126/science.1170944
Acknowledgements
This work was supported by grants from the National Key Technology R&D Program (2014BAI09B13), National Natural Science Foundation of China Grants (30870914, 81270582, 81470290), National Public Health Grand Research Foundation (201202017), Major Program Fund of the Science Technology Department of Zhejiang Province (2013c03043-2), the Foundation of Innovation Team for Basic and Clinical Research of Zhejiang Province (2011R50015), Zhejiang Province Fund for Distinguished Young Scholars (LR12H08001).
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HT and PL designed the study. PL and SZ performed the experiments. PL, DMM and HT wrote the manuscript. PL, YL, SZ and HZ analyzed and arranged the data. HY performed the gene mutation analysis. CH, JW, YR, XZ, CM, LM, WX, LY, ZZ and JJ provided patient samples and data.
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The authors have no conflicts of interest.
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All procedures in the current study were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki declaration and its later amendments.
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Informed consent was obtained from all individual participants included in the study.
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Lin, P., Luo, Y., Zhu, S. et al. Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes. J Cancer Res Clin Oncol 144, 1037–1047 (2018). https://doi.org/10.1007/s00432-018-2627-3
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DOI: https://doi.org/10.1007/s00432-018-2627-3