D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization

References

• Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, et al. IDH1 and IDH2 mutations in gliomas. N Eng J Med. 2009;360:765–73. doi:10.1056/NEJMoa0808710.
   PubMed Web of Science ®Google Scholar
• Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. (New York, NY) 2008;321:1807–12. doi:10.1126/science.1164382. PMID:18772396.
   PubMed Web of Science ®Google Scholar
• Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Eng J Med. 2009;361:1058–66. doi:10.1056/NEJMoa0903840.
   PubMed Web of Science ®Google Scholar
• Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:739–44. doi:10.1038/nature08617. PMID:19935646.
   PubMed Web of Science ®Google Scholar
• Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34. doi:10.1016/j.ccr.2010.01.020. PMID:20171147.
   PubMed Web of Science ®Google Scholar
• Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30. doi:10.1016/j.ccr.2010.12.014. PMID:21251613.
   PubMed Web of Science ®Google Scholar
• Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–67. doi:10.1016/j.ccr.2010.11.015. PMID:21130701.
   PubMed Web of Science ®Google Scholar
• Losman JA, Looper RE, Koivunen P, Lee S, Schneider RK, McMahon C, Cowley GS, Root DE, Ebert BL, Kaelin WG Jr., et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. (New York, NY) 2013;339:1621–5. doi:10.1126/science.1231677. PMID:23393090.
   PubMed Web of Science ®Google Scholar
• Chaturvedi A, Araujo Cruz MM, Jyotsana N, Sharma A, Goparaju R, Schwarzer A, Görlich K, Schottmann R, Struys EA, Jansen EE, et al. Enantiomer-specific and paracrine leukemogenicity of mutant IDH metabolite 2-hydroxyglutarate. Leukemia. 2016;30:1708–15. doi:10.1038/leu.2016.71. PMID:27063596.
   PubMed Web of Science ®Google Scholar
• Shi J, Zuo H, Ni L, Xia L, Zhao L, Gong M, Nie D, Gong P, Cui D, Shi W, et al. An IDH1 mutation inhibits growth of glioma cells via GSH depletion and ROS generation. Neurol Sci. 2014;35:839–45. doi:10.1007/s10072-013-1607-2. PMID:24362902.
   PubMed Web of Science ®Google Scholar
• Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, Spasojevic I, Boros LG, Yang SH, Yan H. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132 h mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. J Biol Chem. 2014;289:23318–28. doi:10.1074/jbc.M114.575183. PMID:24986863.
   PubMed Web of Science ®Google Scholar
• Fu X, Chin RM, Vergnes L, Hwang H, Deng G, Xing Y, Pai MY, Li S, Ta L, Fazlollahi F, et al. 2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling. Cell Metab. 2015;22:508–15. doi:10.1016/j.cmet.2015.06.009. PMID:26190651.
   PubMed Web of Science ®Google Scholar
• Li F, He X, Ye D, Lin Y, Yu H, Yao C, Huang L, Zhang J, Wang F, Xu S, et al. NADP(+)-IDH Mutations Promote Hypersuccinylation that Impairs Mitochondria Respiration and Induces Apoptosis Resistance. Mol Cell. 2015;60:661–75. doi:10.1016/j.molcel.2015.10.017. PMID:26585387.
   PubMed Web of Science ®Google Scholar
• Curti A, Aluigi M, Pandolfi S, Ferri E, Isidori A, Salvestrini V, Durelli I, Horenstein AL, Fiore F, Massaia M, et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia. 2007;21:353–5. doi:10.1038/sj.leu.2404485. PMID:17170728.
   PubMed Web of Science ®Google Scholar
• Aurelius J, Thoren FB, Akhiani AA, Brune M, Palmqvist L, Hansson M, Hellstrand K, Martner A. Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis. Blood. 2012;119:5832–7. doi:10.1182/blood-2011-11-391722. PMID:22550344.
   PubMed Web of Science ®Google Scholar
• Kohanbash G, Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, Chheda ZS, Downey KM, Watchmaker PB, Beppler C, et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J Clin Invest. 2017;127:1425–37. doi:10.1172/JCI90644. PMID:28319047.
   PubMed Web of Science ®Google Scholar
• Xu T, Stewart KM, Wang X, Liu K, Xie M, Ryu JK, Li K, Ma T, Wang H, Ni L, et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature. 2017;548:228–33. PMID:28783731.
   PubMed Web of Science ®Google Scholar
• Yang H, Ye D, Guan KL, Xiong Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res. 2012;18:5562–71. doi:10.1158/1078-0432.CCR-12-1773. PMID:23071358.
   PubMed Web of Science ®Google Scholar
• Balss J, Thiede C, Bochtler T, Okun JG, Saadati M, Benner A, Pusch S, Ehninger G, Schaich M, Ho AD, et al. Pretreatment d-2-hydroxyglutarate serum levels negatively impact on outcome in IDH1-mutated acute myeloid leukemia. Leukemia. 2016;30:782–8. doi:10.1038/leu.2015.317. PMID:26582645.
   PubMed Web of Science ®Google Scholar
• Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T_H17 and T_regcells. J Exp Med. 2011;208:1367–76. doi:10.1084/jem.20110278. PMID:21708926.
   PubMed Web of Science ®Google Scholar
• Choi C, Ganji SK, DeBerardinis RJ, Hatanpaa KJ, Rakheja D, Kovacs Z, Yang XL, Mashimo T, Raisanen JM, Marin-Valencia I, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med. 2012;18:624–9. doi:10.1038/nm.2682. PMID:22281806.
   PubMed Web of Science ®Google Scholar
• Jin G, Reitman ZJ, Spasojevic I, Batinic-Haberle I, Yang J, Schmidt-Kittler O, Bigner DD, Yan H. 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. Plos One. 2011;6:e16812. doi:10.1371/journal.pone.0016812. PMID:21326614.
   PubMed Web of Science ®Google Scholar
• Terunuma A, Putluri N, Mishra P, Mathe EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest. 2014; 124:398–412. doi:10.1172/JCI71180. PMID:24316975.
   PubMed Web of Science ®Google Scholar
• DiNardo CD, Propert KJ, Loren AW, Paietta E, Sun Z, Levine RL, Straley KS, Yen K, Patel JP, Agresta S, et al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia. Blood. 2013;121:4917–24. doi:10.1182/blood-2013-03-493197. PMID:23641016.
   PubMed Web of Science ®Google Scholar
• Gross S, Cairns RA, Minden MD, Driggers EM, Bittinger MA, Jang HG, Sasaki M, Jin S, Schenkein DP, Su SM, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207:339–44. doi:10.1084/jem.20092506. PMID:20142433.
   PubMed Web of Science ®Google Scholar
• Balss J, Pusch S, Beck AC, Herold-Mende C, Kramer A, Thiede C, Buckel W, Langhans CD, Okun JG, von Deimling A. Enzymatic assay for quantitative analysis of (D)-2-hydroxyglutarate. Acta Neuropathol. 2012;124:883–91. doi:10.1007/s00401-012-1060-y. PMID:23117877.
   PubMed Web of Science ®Google Scholar
• Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, Zhao F, Medeiros BC, Tyvoll DA, Majeti R. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84. doi:10.1038/nm.3788. PMID:25599133.
   PubMed Web of Science ®Google Scholar
• Palmer CS, Ostrowski M, Balderson B, Christian N, Crowe SM. Glucose metabolism regulates T cell activation, differentiation, and functions. Front Immunol. 2015;6:1. doi:10.3389/fimmu.2015.00001. PMID:25657648.
   PubMed Web of Science ®Google Scholar
• Ma S, Jiang B, Deng W, Gu ZK, Wu FZ, Li T, Xia Y, Yang H, Ye D, Xiong Y, et al. D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth. Oncotarget. 2015;6:8606–20. doi:10.18632/oncotarget.3330. PMID:25825982.
   PubMedGoogle Scholar
• Goldberg HJ, Whiteside CI, Hart GW, Fantus IG. Posttranslational, reversible O-glycosylation is stimulated by high glucose and mediates plasminogen activator inhibitor-1 gene expression and Sp1 transcriptional activity in glomerular mesangial cells. Endocrinol. 2006;147:222–31. doi:10.1210/en.2005-0523..
   PubMed Web of Science ®Google Scholar
• Jozwiak P, Forma E, Brys M, Krzeslak A. O-Glcnacylation and metabolic reprograming in cancer. Front Endocrinol. 2014;5:145.
   PubMed Web of Science ®Google Scholar
• Bottcher M, Hofmann AD, Bruns H, Haibach M, Loschinski R, Saul D, Mackensen A, Le Blanc K, Jitschin R, Mougiakakos D. Mesenchymal stromal cells disrupt mTOR-signaling and aerobic glycolysis during T-cell activation. Stem Cells. 2016;34:516–21. doi:10.1002/stem.2234. PMID:26485560.
   PubMed Web of Science ®Google Scholar
• Latini A, Scussiato K, Rosa RB, Llesuy S, Bello-Klein A, Dutra-Filho CS, Wajner M. D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats. Eur J Neurosci. 2003;17:2017–22. doi:10.1046/j.1460-9568.2003.02639.x. PMID:12786967.
   PubMed Web of Science ®Google Scholar
• Jitschin R, Hofmann AD, Bruns H, Giessl A, Bricks J, Berger J, Saul D, Eckart MJ, Mackensen A, Mougiakakos D. Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia. Blood. 2014;123:2663–72. doi:10.1182/blood-2013-10-532200. PMID:24553174.
   PubMed Web of Science ®Google Scholar
• Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. (Baltimore, Md: 1950) 2011;186:3299–303. doi:10.4049/jimmunol.1003613. PMID:21317389.
   PubMed Web of Science ®Google Scholar
• Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who's who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol. 2013;43:2797–809. doi:10.1002/eji.201343751. PMID:24258910.
   PubMed Web of Science ®Google Scholar
• O'Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, Qiu J, Smith AM, Lam WY, DiPlato LM, et al. Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity. 2014;41:75–88. doi:10.1016/j.immuni.2014.06.005. PMID:25001241.
   PubMed Web of Science ®Google Scholar
• Schieke SM, Phillips D, McCoy JP, Jr., Aponte AM, Shen RF, Balaban RS, Finkel T. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006;281:27643–52. doi:10.1074/jbc.M603536200. PMID:16847060.
   PubMed Web of Science ®Google Scholar
• Buller CL, Loberg RD, Fan MH, Zhu Q, Park JL, Vesely E, Inoki K, Guan KL, Brosius FC 3rd. A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression. A J Physiol Cell Physiol. 2008;295:C836–43. doi:10.1152/ajpcell.00554.2007.
   PubMed Web of Science ®Google Scholar
• Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev. 2012;249:43–58. doi:10.1111/j.1600-065X.2012.01152.x. PMID:22889214.
   PubMed Web of Science ®Google Scholar
• Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Nat Acad Sci U S A. 2011;108:4129–34. doi:10.1073/pnas.1014769108.
   PubMed Web of Science ®Google Scholar
• Carbonneau M, L MG, Lalonde ME, Germain MA, Motorina A, Guiot MC, Secco B, Vincent EE, Tumber A, Hulea L, et al. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat Commun. 2016;7:12700. doi:10.1038/ncomms12700. PMID:27624942.
   PubMed Web of Science ®Google Scholar
• Land SC, Tee AR. Hypoxia-inducible factor 1alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem. 2007; 282:20534–43. doi:10.1074/jbc.M611782200. PMID:17502379.
   PubMed Web of Science ®Google Scholar
• Koivunen P, Lee S, Duncan CG, Lopez G, Lu G, Ramkissoon S, Losman JA, Joensuu P, Bergmann U, Gross S, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483:484–8. doi:10.1038/nature10898. PMID:22343896.
   PubMed Web of Science ®Google Scholar
• Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208:1367–76. doi:10.1084/jem.20110278. PMID:21708926.
   PubMed Web of Science ®Google Scholar
• Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 2016;24:657–71. doi:10.1016/j.cmet.2016.08.011. PMID:27641098.
   PubMed Web of Science ®Google Scholar
• Berghoff AS, Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurscheid S, Kresl P, Wöhrer A, Marosi C, Hegi ME, et al. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro-Oncol. 2017;19:1460–8. doi:10.1093/neuonc/nox054.
   PubMed Web of Science ®Google Scholar
• Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Velica P, You J, Chia GS, Sim J, Doedens A, et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature. 2016;540:236–41. doi:10.1038/nature20165. PMID:27798602.
   PubMed Web of Science ®Google Scholar
• Buck MD, O'Sullivan D, Pearce EL. T cell metabolism drives immunity. J Exp Med. 2015;212:1345–60. doi:10.1084/jem.20151159. PMID:26261266.
   PubMed Web of Science ®Google Scholar
• Chang CH, Pearce EL. Emerging concepts of T cell metabolism as a target of immunotherapy. Na Immunol. 2016;17:364–8. doi:10.1038/ni.3415.
   PubMed Web of Science ®Google Scholar
• Sulkowski PL, Corso CD, Robinson ND, Scanlon SE, Purshouse KR, Bai H, Liu Y, Sundaram RK, Hegan DC, Fons NR, et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci Translational Med. 2017;9. doi:10.1126/scitranslmed.aal2463.
   PubMed Web of Science ®Google Scholar
• Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM, Gray NS, Sabatini DM. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873–86. doi:10.1016/j.cell.2009.03.046. PMID:19446321.
   PubMed Web of Science ®Google Scholar
• Achouri Y, Noel G, Vertommen D, Rider MH, Veiga-Da-Cunha M, Van Schaftingen E. Identification of a dehydrogenase acting on D-2-hydroxyglutarate. The Biochem J. 2004;381:35–42. doi:10.1042/BJ20031933..
   PubMed Web of Science ®Google Scholar
• Firth JD, Ebert BL, Ratcliffe PJ. Hypoxic regulation of lactate dehydrogenase A. Interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem. 1995;270:21021–7. doi:10.1074/jbc.270.36.21021. PMID:7673128.
   PubMed Web of Science ®Google Scholar
• Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metabol. 2006;3:187–97. doi:10.1016/j.cmet.2006.01.012.
   PubMed Web of Science ®Google Scholar
• He G, Jiang Y, Zhang B, Wu G. The effect of HIF-1alpha on glucose metabolism, growth and apoptosis of pancreatic cancerous cells. Asia Pacific Jclin Nutrition. 2014;23:174–80.
   PubMed Web of Science ®Google Scholar
• Mougiakakos D, Johansson CC, Kiessling R. Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood. 2009;113:3542–5. doi:10.1182/blood-2008-09-181040. PMID:19050306.
   PubMed Web of Science ®Google Scholar
• Mougiakakos D, Johansson CC, Jitschin R, Bottcher M, Kiessling R. Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood. 2011;117:857–61. doi:10.1182/blood-2010-09-307041. PMID:21030559.
   PubMed Web of Science ®Google Scholar
• Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metabol. 2017;25:1282–93.e7. doi:10.1016/j.cmet.2016.12.018.
   PubMed Web of Science ®Google Scholar
• Kishton RJ, Sukumar M, Restifo NP. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metabol. 2017;26:94–109. doi:10.1016/j.cmet.2017.06.016.
   PubMed Web of Science ®Google Scholar
• Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38:225–36. doi:10.1016/j.immuni.2012.10.020. PMID:23415911.
   PubMed Web of Science ®Google Scholar
• Kaminski MM, Sauer SW, Klemke CD, Suss D, Okun JG, Krammer PH, Gülow K. Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol. (Baltimore, Md: 1950) 2010;184:4827–41. doi:10.4049/jimmunol.0901662. PMID:20335530.
   PubMed Web of Science ®Google Scholar
• Pouyssegur J, Mechta-Grigoriou F. Redox regulation of the hypoxia-inducible factor. Biol Chem. 2006;387:1337–46. doi:10.1515/BC.2006.167. PMID:17081104.
   PubMed Web of Science ®Google Scholar
• Han Y, Ye A, Bi L, Wu J, Yu K, Zhang S. Th17 cells and interleukin-17 increase with poor prognosis in patients with acute myeloid leukemia. Cancer Sci. 2014;105:933–42. doi:10.1111/cas.12459. PMID:24890519.
   PubMed Web of Science ®Google Scholar
• Tian T, Yu S, Liu L, Xue F, Yuan C, Wang M, Ji C, Ma D. The profile of T helper subsets in bone marrow microenvironment is distinct for different stages of acute myeloid leukemia patients and chemotherapy partly ameliorates these variations. Plos One. 2015;10:e0131761. doi:10.1371/journal.pone.0131761. PMID:26134277.
   PubMed Web of Science ®Google Scholar
• Abousamra NK, Salah El-Din M, Helal R. Prognostic value of Th17 cells in acute leukemia. Med Oncol. (Northwood, London, England) 2013;30:732. doi:10.1007/s12032-013-0732-3. PMID:24085544.
   PubMed Web of Science ®Google Scholar
• Wu C, Wang S, Wang F, Chen Q, Peng S, Zhang Y, Qian J, Jin J, Xu H. Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol. 2009;158:199–204. doi:10.1111/j.1365-2249.2009.04011.x. PMID:19737137.
   PubMed Web of Science ®Google Scholar
• Tian T, Yu S, Wang M, Yuan C, Zhang H, Ji C, Ma D. Aberrant T helper 17 cells and related cytokines in bone marrow microenvironment of patients with acute myeloid leukemia. Clin Dev Immunol. 2013;2013:915873. doi:10.1155/2013/915873. PMID:24023567.
   PubMedGoogle Scholar
• Peck A, Mellins ED. Precarious balance: Th17 cells in host defense. Infect Immun. 2010;78:32–8. doi:10.1128/IAI.00929-09. PMID:19901061.
   PubMed Web of Science ®Google Scholar
• Jagarlamudi R, Kumar L, Kochupillai V, Kapil A, Banerjee U, Thulkar S. Infections in acute leukemia: an analysis of 240 febrile episodes. Med Oncol. (Northwood, London, England) 2000;17:111–6. doi:10.1007/BF02796205. PMID:10871816.
   PubMed Web of Science ®Google Scholar