Mutant IDH: A Targetable Driver of Leukemic Phenotypes Linking Metabolism, Epigenetics and Transcriptional Regulation

References

• Cancer Genome Atlas Research Network . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia . N. Engl. J. Med.368 ( 22 ), 2059 – 2074 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Meyer SC , LevineRL . Translational implications of somatic genomics in acute myeloid leukaemia . Lancet Oncol.15 ( 9 ), e382 – e394 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Mardis ER , DingL , DoolingDJet al. Recurring mutations found by sequencing an acute myeloid leukemia genome . N. Engl. J. Med.361 ( 11 ), 1058 – 1066 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Wang ZY , ChenZ . Acute promyelocytic leukemia: from highly fatal to highly curable . Blood111 ( 5 ), 2505 – 2515 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Stone RM , MandrekarS , SanfordBLet al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]) . Blood (ASH Annual Meeting Abstracts)126 ( 23 ), 6 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Kantarjian HM , ThomasXG , DmoszynskaAet al. Multicenter, randomized, open-label, Phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia . J. Clin. Oncol.30 ( 21 ), 2670 – 2677 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Reitman ZJ , YanH . Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism . J. Natl Cancer Inst.102 ( 13 ), 932 – 941 ( 2010 ).
   PubMedGoogle Scholar
• Deberardinis RJ , MancusoA , DaikhinEet al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis . Proc. Natl Acad. Sci. USA104 ( 49 ), 19345 – 19350 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Metallo CM , GameiroPA , BellELet al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia . Nature481 ( 7381 ), 380 – 384 ( 2012 ).
   Web of Science ®Google Scholar
• Parsons DW , JonesS , ZhangXet al. An integrated genomic analysis of human glioblastoma multiforme . Science321 ( 5897 ), 1807 – 1812 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Patel JP , GonenM , FigueroaMEet al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia . N. Engl. J. Med.366 ( 12 ), 1079 – 1089 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Green CL , EvansCM , HillsRK , BurnettAK , LinchDC , GaleRE . The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status . Blood116 ( 15 ), 2779 – 2782 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Green CL , EvansCM , ZhaoLet al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation . Blood118 ( 2 ), 409 – 412 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Zhao S , LinY , XuWet al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha . Science324 ( 5924 ), 261 – 265 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Dang L , JinS , SuSM . IDH mutations in glioma and acute myeloid leukemia . Trends Mol. Med.16 ( 9 ), 387 – 397 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Dang L , WhiteDW , GrossSet al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate . Nature462 ( 7274 ), 739 – 744 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Ward PS , PatelJ , WiseDRet al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate . Cancer Cell17 ( 3 ), 225 – 234 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Sasaki M , KnobbeCB , MungerJCet al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics . Nature488 ( 7413 ), 656 – 659 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Chaturvedi A , Araujo CruzMM , JyotsanaNet al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML . Blood122 ( 16 ), 2877 – 2887 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kats LM , ReschkeM , TaulliRet al. Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance . Cell Stem Cell14 ( 3 ), 329 – 341 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Gross S , CairnsRA , MindenMDet al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations . J. Exp. Med.207 ( 2 ), 339 – 344 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Gao J , AksoyBA , DogrusozUet al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal . Sci. Signal.6 ( 269 ), pl1 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Cerami E , GaoJ , DogrusozUet al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data . Cancer Discov.2 ( 5 ), 401 – 404 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Figueroa ME , LugthartS , LiYet al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia . Cancer Cell17 ( 1 ), 13 – 27 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Figueroa ME , Abdel-WahabO , LuCet al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation . Cancer Cell18 ( 6 ), 553 – 567 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Rampal R , AlkalinA , MadzoJet al. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia . Cell Rep.9 ( 5 ), 1841 – 1855 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Akalin A , Garrett-BakelmanFE , KormakssonMet al. Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia . PLoS Genet.8 ( 6 ), e1002781 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Tahiliani M , KohKP , ShenYet al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 . Science324 ( 5929 ), 930 – 935 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Stroud H , FengS , Morey KinneyS , PradhanS , JacobsenSE . 5-hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells . Genome Biol.12 ( 6 ), R54 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Yu M , HonGC , SzulwachKEet al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome . Cell149 ( 6 ), 1368 – 1380 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Ficz G , BrancoMR , SeisenbergerSet al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation . Nature473 ( 7347 ), 398 – 402 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Pastor WA , PapeUJ , HuangYet al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells . Nature473 ( 7347 ), 394 – 397 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Szulwach KE , LiX , LiYet al. Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells . PLoS Genet.7 ( 6 ), e1002154 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Williams K , ChristensenJ , PedersenMTet al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity . Nature473 ( 7347 ), 343 – 348 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Wu H , D’AlessioAC , ItoSet al. Genome-wide analysis of 5-hydroxymethylcytosine distribution reveals its dual function in transcriptional regulation in mouse embryonic stem cells . Genes Dev.25 ( 7 ), 679 – 684 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Xu Y , WuF , TanLet al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells . Mol. Cell42 ( 4 ), 451 – 464 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Marcucci G , MaharryK , WuYZet al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study . J. Clin. Oncol.28 ( 14 ), 2348 – 2355 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Gaidzik VI , PaschkaP , SpathDet al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group . J. Clin. Oncol.30 ( 12 ), 1350 – 1357 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• He YF , LiBZ , LiZet al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA . Science333 ( 6047 ), 1303 – 1307 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Xu W , YangH , LiuYet al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases . Cancer Cell19 ( 1 ), 17 – 30 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Wang Y , XiaoM , ChenXet al. WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation . Mol. Cell57 ( 4 ), 662 – 673 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Suganuma T , WorkmanJL . Signals and combinatorial functions of histone modifications . Annu. Rev. Biochem.80 , 473 – 499 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Chi P , AllisCD , WangGG . Covalent histone modifications-miswritten, misinterpreted and mis-erased in human cancers . Nat. Rev. Cancer10 ( 7 ), 457 – 469 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Chowdhury R , YeohKK , TianYMet al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases . EMBO Rep.12 ( 5 ), 463 – 469 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Kernytsky A , WangF , HansenEet al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition . Blood125 ( 2 ), 296 – 303 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Turcan S , RohleD , GoenkaAet al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype . Nature483 ( 7390 ), 479 – 483 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Lu C , WardPS , KapoorGSet al. IDH mutation impairs histone demethylation and results in a block to cell differentiation . Nature483 ( 7390 ), 474 – 478 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Jones PA . Functions of DNA methylation: islands, start sites, gene bodies and beyond . Nat. Rev. Genet.13 ( 7 ), 484 – 492 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Rao SS , HuntleyMH , DurandNCet al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping . Cell159 ( 7 ), 1665 – 1680 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Flavahan WA , DrierY , LiauBBet al. Insulator dysfunction and oncogene activation in IDH mutant gliomas . Nature529 ( 7584 ), 110 – 114 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Rasmussen KD , JiaG , JohansenJVet al. Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis . Genes Dev.29 ( 9 ), 910 – 922 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Lev Maor G , YearimA , AstG . The alternative role of DNA methylation in splicing regulation . Trends Genet.31 ( 5 ), 274 – 280 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Barski A , CuddapahS , CuiKet al. High-resolution profiling of histone methylations in the human genome . Cell129 ( 4 ), 823 – 837 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Greer EL , ShiY . Histone methylation: a dynamic mark in health, disease and inheritance . Nat. Rev. Genet.13 ( 5 ), 343 – 357 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Berger SL . The complex language of chromatin regulation during transcription . Nature447 ( 7143 ), 407 – 412 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Wagner EJ , CarpenterPB . Understanding the language of Lys36 methylation at histone H3 . Nat. Rev. Mol. Cell Biol.13 ( 2 ), 115 – 126 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Friedman AD . Transcriptional control of granulocyte and monocyte development . Oncogene26 ( 47 ), 6816 – 6828 ( 2007 ).
   PubMed Web of Science ®Google Scholar
• Kallin EM , Rodriguez-UbrevaJ , ChristensenJet al. Tet2 facilitates the derepression of myeloid target genes during CEBPalpha-induced transdifferentiation of pre-B cells . Mol. Cell48 ( 2 ), 266 – 276 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• De La Rica L , Rodriguez-UbrevaJ , GarciaMet al. PU.1 target genes undergo Tet2-coupled demethylation and DNMT3b-mediated methylation in monocyte-to-osteoclast differentiation . Genome Biol.14 ( 9 ), R99 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Keith B , JohnsonRS , SimonMC . HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression . Nat. Rev. Cancer12 ( 1 ), 9 – 22 ( 2012 ).
   Web of Science ®Google Scholar
• Koivunen P , LeeS , DuncanCGet al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation . Nature483 ( 7390 ), 484 – 488 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Losman JA , LooperRE , KoivunenPet al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible . Science339 ( 6127 ), 1621 – 1625 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Adkins NL , GeorgelPT . MeCP2: structure and function . Biochem. Cell Biol.89 ( 1 ), 1 – 11 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Maunakea AK , ChepelevI , CuiK , ZhaoK . Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition . Cell Res.23 ( 11 ), 1256 – 1269 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Mellen M , AyataP , DewellS , KriaucionisS , HeintzN . MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system . Cell151 ( 7 ), 1417 – 1430 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Wang F , TravinsJ , DelabarreBet al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation . Science340 ( 6132 ), 622 – 626 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Chen C , LiuY , LuCet al. Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition . Genes Dev.27 ( 18 ), 1974 – 1985 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Mylonas E , JaninM , BawaOet al. Isocitrate dehydrogenase (IDH)2 R140Q mutation induces myeloid and lymphoid neoplasms in mice . Leukemia28 ( 6 ), 1343 – 1346 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Cairns RA , IqbalJ , LemonnierFet al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma . Blood119 ( 8 ), 1901 – 1903 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Kroon E , KroslJ , ThorsteinsdottirU , BabanS , BuchbergAM , SauvageauG . Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b . EMBO J.17 ( 13 ), 3714 – 3725 ( 1998 ).
   PubMed Web of Science ®Google Scholar
• Li L , PilotoO , NguyenHBet al. Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model . Blood111 ( 7 ), 3849 – 3858 ( 2008 ).
   PubMed Web of Science ®Google Scholar
• Wang J , LiuY , LiZet al. Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia . Blood116 ( 26 ), 5991 – 6002 ( 2010 ).
   PubMed Web of Science ®Google Scholar
• Rohle D , Popovici-MullerJ , PalaskasNet al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells . Science340 ( 6132 ), 626 – 630 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Li L , PazAC , WilkyBAet al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells . PLoS ONE10 ( 9 ), e0133813 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Chaturvedi A , CruzMMA , GoparajuRet al. A novel inhibitor of mutant IDH1 induces differentiation in vivo and prolongs survival in a mouse model of leukemia . Blood124 ( 21 ), 3598 – 3598 ( 2014 ).
   Web of Science ®Google Scholar
• Okoye-Okafor UC , BartholdyB , CartierJet al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia . Nat. Chem. Biol.11 ( 11 ), 878 – 886 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Stein EM , DinardoC , AltmanJKet al. Safety and efficacy of AG-221, a potent inhibitor of mutant IDH2 that promotes differentiation of myeloid cells in patients with advanced hematologic malignancies: results of a Phase 1/2 trial . Blood123 ( 23 ), 323 ( 2015 ).
   Google Scholar
• Fathi AT , SadrzadehH , BorgerDRet al. Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response . Blood120 ( 23 ), 4649 – 4652 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Dinardo CD , PropertKJ , LorenAWet al. Serum 2-hydroxyglutarate levels predict isocitrate dehydrogenase mutations and clinical outcome in acute myeloid leukemia . Blood121 ( 24 ), 4917 – 4924 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Filippakopoulos P , KnappS . Targeting bromodomains: epigenetic readers of lysine acetylation . Nat. Rev. Drug Discov.13 ( 5 ), 337 – 356 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Herrmann H , BlattK , ShiJet al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML . Oncotarget3 ( 12 ), 1588 – 1599 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Chan SM , MedeirosBC , MajetiR . BCL-2 inhibition as a synthetic lethal approach to target isocitrate dehydrogenase mutations in acute myeloid leukemia stem cells . Blood (ASH Annual Meeting Abstracts)122 ( 21 ), 885 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Emadi A , JunSA , TsukamotoT , FathiAT , MindenMD , DangCV . Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations . Exp. Hematol.42 ( 4 ), 247 – 251 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Cardaci S , CirioloMR . TCA cycle defects and cancer: when metabolism tunes redox state . Int. J. Cell Biol.2012 , 161837 ( 2012 ).
   PubMedGoogle Scholar
• Reitman ZJ , JinG , KarolyEDet al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome . Proc. Natl Acad. Sci. USA108 ( 8 ), 3270 – 3275 ( 2011 ).
   PubMed Web of Science ®Google Scholar