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Review

Identifying high-risk adult AML patients: epigenetic and genetic risk factors and their implications for therapy

, , &
Pages 351-360 | Received 16 Oct 2015, Accepted 11 Jan 2016, Published online: 12 Feb 2016

References

  • Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–2074.
  • Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–474.
  • Marcucci G, Haferlach T, Dohner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5):475–486.
  • Foran JM. New prognostic markers in acute myeloid leukemia: perspective from the clinic. Hematology Am Soc Hematol Educ Program. 2010;2010:47–55.
  • Roug AS, Hansen MC, Nederby L, et al. Diagnosing and following adult patients with acute myeloid leukaemia in the genomic age. Br J Haematol. 2014;167(2):162–176.
  • Graubert TA, Brunner AM, Fathi AT. New molecular abnormalities and clonal architecture in AML: from reciprocal translocations to whole-genome sequencing. Am Soc Clin Oncol Educ Book. 2014;e334–340. doi:10.14694/EdBook_AM.2014.34.e334
  • Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011;29(5):487–494.
  • Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354–365.
  • Yohe S. Molecular genetic markers in acute myeloid leukemia. J Clin Med. 2015;4(3):460–478.
  • Yanada M, Kurosawa S, Yamaguchi T, et al. Prognosis of acute myeloid leukemia harboring monosomal karyotype in patients treated with or without allogeneic hematopoietic cell transplantation after achieving complete remission. Haematologica. 2012;97(6):915–918.
  • Breems DA, Van Putten WL, De Greef GE, et al Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26(29):4791–4797.
  • Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119(9):2114–2121.
  • Kayser S, Zucknick M, Dohner K, et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood. 2012;119(2):551–558.
  • Voutiadou G, Papaioannou G, Gaitatzi M, et al. Monosomal karyotype in acute myeloid leukemia defines a distinct subgroup within the adverse cytogenetic risk category. Cancer Genet. 2013;206(1–2):32–36.
  • Downie B, Stone R, Rizzieri D, et al. Monosomal karyotype is predictive of poor response to therapy and worse overall survival in secondary acute myeloid leukemia (sAML): analysis of a multi-center phase II study of amonafide and cytarabine induction therapy. Blood. 2009;114(22):2076.
  • Perrot A, Luquet I, Pigneux A, et al. Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities. Blood. 2011;118(3):679–685.
  • Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100(13):4325–4336.
  • Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937–951.
  • O’Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, version 2.2013. J Natl Compr Canc Netw. 2013;11(9):1047–1055.
  • Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 2013;121(18):3563–3572.
  • Buchner T, Berdel WE, Haferlach C, et al. Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol. 2009;27(1):61–69.
  • Fung TK, So CW. Overcoming treatment resistance in acute promyelocytic leukemia and beyond. Oncotarget. 2013;4(8):1128–1129.
  • Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–121.
  • Alcalay M, Meani N, Gelmetti V, et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J Clin Invest. 2003;112(11):1751-1761).
  • Krejci O, Wunderlich M, Geiger H, et al. p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death. Blood. 2008;111(4):2190–2199.
  • Viale A, De Franco F, Orleth A, et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature. 2009;457(7225):51–56.
  • Casorelli I, Tenedini E, Tagliafico E, et al. Identification of a molecular signature for leukemic promyelocytes and their normal counterparts: Focus on DNA repair genes. Leukemia. 2006;20(11):1978–1988.
  • Boichuk S, Hu L, Makielski K, et al. Functional connection between Rad51 and PML in homology-directed repair. PLoS One. 2011;6(10):e25814.
  • Yeung PL, Denissova NG, Nasello C, et al. Promyelocytic leukemia nuclear bodies support a late step in DNA double-strand break repair by homologous recombination. J Cell Biochem. 2012;113(5):1787–1799.
  • Zhong S, Hu P, Ye TZ, et al. A role for PML and the nuclear body in genomic stability. Oncogene. 1999;18(56):7941–7947.
  • Suhasini AN, Brosh RM Jr. Fanconi anemia and Bloom’s syndrome crosstalk through FANCJ-BLM helicase interaction. Trends Genet. 2012;28(1):7–13.
  • Poppe B, Van Limbergen H, Van Roy N, et al. Chromosomal aberrations in Bloom syndrome patients with myeloid malignancies. Cancer Genetics and Cytogenetics. 2001;128(1):39–42.
  • Schoch C, Kern W, Kohlmann A, et al. Acute myeloid leukemia with a complex aberrant karyotype is a distinct biological entity characterized by genomic imbalances and a specific gene expression profile. Genes Chromosomes Cancer. 2005;43(3):227–238.
  • Cavelier C, Didier C, Prade N, et al. Constitutive activation of the DNA damage signaling pathway in acute myeloid leukemia with complex karyotype: potential importance for checkpoint targeting therapy. Cancer Res. 2009;69(22):8652–8661.
  • Esposito MT, So CW. DNA damage accumulation and repair defects in acute myeloid leukemia: implications for pathogenesis, disease progression, and chemotherapy resistance. Chromosoma. 2014;123(6):545–561.
  • Jawad M, Seedhouse CH, Russell N, et al. Polymorphisms in human homeobox HLX1 and DNA repair RAD51 genes increase the risk of therapy-related acute myeloid leukemia. Blood. 2006;108(12):3916–3918.
  • Allan JM, Smith AG, Wheatley K, et al. Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy. Blood. 2004;104(13):3872–3877.
  • Strom SS, Estey E, Outschoorn UM, et al. Acute myeloid leukemia outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients. Leuk Lymphoma. 2010;51(4):598–605.
  • Monzo M, Brunet S, Urbano-Ispizua A, et al. Genomic polymorphisms provide prognostic information in intermediate-risk acute myeloblastic leukemia. Blood. 2006;107(12):4871–4879.
  • Seedhouse C, Faulkner R, Ashraf N, et al. Polymorphisms in genes involved in homologous recombination repair interact to increase the risk of developing acute myeloid leukemia. Clin Cancer Res. 2004;10(8):2675–2680.
  • Hasselbach L, Haase S, Fischer D, et al. Characterisation of the promoter region of the human DNA-repair gene Rad51. Eur J Gynaecol Oncol. 2005;26(6):589–598.
  • Vispe S, Cazaux C, Lesca C, et al. Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. Nucleic Acids Res. 1998;26(12):2859–2864.
  • Hamdy MS, El-Haddad AM, Bahaa El-Din NM, et al. RAD51 and XRCC3 gene polymorphisms and the risk of developing acute myeloid leukemia. J Investig Med. 2011;59(7):1124–1130.
  • Banescu C, Duicu C, Trifa AP, et al. XRCC1 Arg194Trp and Arg399Gln polymorphisms are significantly associated with shorter survival in acute myeloid leukemia. Leuk Lymphoma. 2014;55(2):365–370.
  • Huang Y, Xie D, Tang N, et al. XRCC1 Arg399Gln variation and leukemia susceptibility: evidence from 2,647 cases and 5,518 controls. Tumour Biol. 2014;35(1):799–808.
  • Wang Y, Spitz MR, Zhu Y, et al. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair (Amst). 2003;2(8):901–908.
  • Das-Gupta EP, Seedhouse CH, Russell NH. Microsatellite instability occurs in defined subsets of patients with acute myeloblastic leukaemia. Br J Haematol. 2001;114(2):307–312.
  • Sheikhha MH, Tobal K, Liu Yin JA. High level of microsatellite instability but not hypermethylation of mismatch repair genes in therapy-related and secondary acute myeloid leukaemia and myelodysplastic syndrome. Br J Haematol. 2002;117(2):359–365.
  • Zhu YM, Das-Gupta EP, Russell NH. Microsatellite instability and p53 mutations are associated with abnormal expression of the MSH2 gene in adult acute leukemia. Blood. 1999;94(2):733–740.
  • Mao G, Yuan F, Absher K, et al. Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: potential contribution to AML progression. Cell Res. 2008;18(2):281–289.
  • Seedhouse CH, Das-Gupta EP, Russell NH. Methylation of the hMLH1 promoter and its association with microsatellite instability in acute myeloid leukemia. Leukemia. 2003;17(1):83–88.
  • Zhang Y, Jasin M. An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nature Structural & Molecular Biology. 2011;18(1):80–84.
  • Simsek D, Brunet E, Wong SY, et al. DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. Plos Genetics. 2011;7(6):e1002080.
  • Lieber MR. NHEJ and its backup pathways in chromosomal translocations. Nature Structural & Molecular Biology. 2010;17(4):393–395.
  • Mistry AR, Felix CA, Whitmarsh RJ, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352(15):1529–1538.
  • Cowell IG, Sondka Z, Smith K, et al. Model for MLL translocations in therapy-related leukemia involving topoisomerase IIbeta-mediated DNA strand breaks and gene proximity. Proc Natl Acad Sci U S A. 2012;109(23):8989–8994.
  • Mrozek K, Marcucci G, Paschka P, et al. Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109(2):431–448.
  • Haferlach C, Kern W, Schindela S, et al. Gene expression of BAALC, CDKN1B, ERG, and MN1 adds independent prognostic information to cytogenetics and molecular mutations in adult acute myeloid leukemia. Genes Chromosomes Cancer. 2012;51(3):257–265.
  • Dohner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106(12):3740–3746.
  • Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3(9):650–665.
  • Zeisig BB, Kulasekararaj AG, Mufti GJ, et al. SnapShot: Acute myeloid leukemia. Cancer Cell. 2012;22(5):698–698 e691.
  • Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358(18):1909–1918.
  • Moore AS, Faisal A, Gonzalez De Castro D, et al. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia. 2012;26(7):1462–1470.
  • Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19(8):1345–1349.
  • Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111(5):2776–2784.
  • Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326–4335.
  • Pratz KW, Sato T, Murphy KM, et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood. 2010;115(7):1425–1432.
  • Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106(12):3733–3739.
  • Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011–4020.
  • Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–1089.
  • Koschmieder S, Halmos B, Levantini E, et al. Dysregulation of the C/EBPalpha differentiation pathway in human cancer. J Clin Oncol. 2009;27(4):619–628.
  • Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001;27(3):263–270.
  • Frohling S, Schlenk RF, Stolze I, et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol. 2004;22(4):624–633.
  • Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA, et al. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113(13):3088–3091.
  • Green CL, Koo KK, Hills RK, et al. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28(16):2739–2747.
  • Dufour A, Schneider F, Metzeler KH, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28(4):570–577.
  • Tang JL, Hou HA, Chen CY, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood. 2009;114(26):5352–5361.
  • Schnittger S, Dicker F, Kern W, et al. RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood. 2011;117(8):2348–2357.
  • Kadia TM, Kantarjian H, Kornblau S, et al. Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS. Cancer. 2012;118(22):5550–5559.
  • Neubauer A, Maharry K, Mrozek K, et al. Patients with acute myeloid leukemia and RAS mutations benefit most from postremission high-dose cytarabine: a Cancer and Leukemia Group B study. J Clin Oncol. 2008;26(28):4603–4609.
  • Maicas M, Vazquez I, Vicente C, et al. Functional characterization of the promoter region of the human EVI1 gene in acute myeloid leukemia: RUNX1 and ELK1 directly regulate its transcription. Oncogene. 2013;32(16):2069–2078.
  • Wieser R. The oncogene and developmental regulator EVI1: expression, biochemical properties, and biological functions. Gene. 2007;396(2):346–357.
  • Laricchia-Robbio L, Fazzina R, Li D, et al. Point mutations in two EVI1 Zn fingers abolish EVI1-GATA1 interaction and allow erythroid differentiation of murine bone marrow cells. Mol Cell Biol. 2006;26(20):7658–7666.
  • Laricchia-Robbio L, Premanand K, Rinaldi CR, et al. EVI1 Impairs myelopoiesis by deregulation of PU.1 function. Cancer Res. 2009;69(4):1633–1642.
  • Senyuk V, Sinha KK, Li D, et al. Repression of RUNX1 activity by EVI1: a new role of EVI1 in leukemogenesis. Cancer Res. 2007;67(12):5658–5666.
  • Langabeer SE, Rogers JR, Harrison G, et al. EVI1 expression in acute myeloid leukaemia. Br J Haematol. 2001;112(1):208–211.
  • Lugthart S, van Drunen E, van Norden Y, et al. High EVI1 levels predict adverse outcome in acute myeloid leukemia: prevalence of EVI1 overexpression and chromosome 3q26 abnormalities underestimated. Blood. 2008;111(8):4329–4337.
  • Bou Samra E, Klein B, Commes T, et al. Development of gene expression-based risk score in cytogenetically normal acute myeloid leukemia patients. Oncotarget. 2012;3(8):824–832.
  • Bullinger L, Dohner K, Bair E, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med. 2004;350(16):1605–1616.
  • Radmacher MD, Marcucci G, Ruppert AS, et al. Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study. Blood. 2006;108(5):1677–1683.
  • Metzeler KH, Hummel M, Bloomfield CD, et al. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood. 2008;112(10):4193–4201.
  • Kondo Y. Epigenetic cross-talk between DNA methylation and histone modifications in human cancers. Yonsei Med J. 2009;50(4):455–463.
  • Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–2433.
  • Thiede C. Mutant DNMT3A: teaming up to transform. Blood. 2012;119(24):5615–5617.
  • Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human leukemia. Oncogene. 2010;29(25):3723–3731.
  • Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012;119(24):5824–5831.
  • Shen Y, Zhu YM, Fan X, et al. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood. 2011;118(20):5593–5603.
  • Metzeler KH, Maharry K, Radmacher MD, et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2011;29(10):1373–1381.
  • Chou WC, Chou SC, Liu CY, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. 2011;118(14):3803–3810.
  • Meldi KM, Figueroa ME. Cytosine modifications in myeloid malignancies. Pharmacol Ther. 2015;152:42–53.
  • Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature. 2010;468(7325):839–843.
  • Moran-Crusio K, Reavie L, Shih A, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.
  • Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114(1):144–147.
  • Gaidzik VI, Paschka P, Spath D, et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. J Clin Oncol. 2012;30(12):1350–1357.
  • Weissmann S, Alpermann T, Grossmann V, et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia. 2012;26(5):934–942.
  • Cao R, Wang L, Wang H, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298(5595):1039–1043.
  • Majewski IJ, Ritchie ME, Phipson B, et al. Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood. 2010;116(5):731–739.
  • Kamminga LM, Bystrykh LV, De Boer A, et al The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood. 2006;107(5):2170–2179.
  • Chou RH, Yu YL, Hung MC. The roles of EZH2 in cell lineage commitment. Am J Transl Res. 2011;3(3):243–250.
  • Mochizuki-Kashio M, Mishima Y, Miyagi S, et al. Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood. 2011;118(25):6553–6561.
  • Herrera-Merchan A, Arranz L, Ligos JM, et al. Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease. Nature Communications. 2012;3:623.
  • Xie H, Xu J, Hsu JH, et al. Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell. 2014;14(1):68–80.
  • Mochizuki-Kashio M, Aoyama K, Sashida G, et al. Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood. 2015;126(10):1172–1183.
  • Grubach L, Juhl-Christensen C, Rethmeier A, et al. Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia. Eur J Haematol. 2008;81(2):112–122.
  • Xu F, Li X, Wu L, et al. Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol. 2011;90(6):643–653.
  • Khan SN, Jankowska AM, Mahfouz R, et al. Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies. Leukemia. 2013;27(6):1301–1309.
  • Sashida G, Harada H, Matsui H, et al. Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation. Nature Communications. 2014;5:4177.
  • Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361(11):1058–1066.
  • Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–567.
  • Green CL, Evans CM, Hills RK, et al. The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood. 2010;116(15):2779–2782.
  • Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118(2):409–412.
  • Koszarska M, Bors A, Feczko A, et al. Type and location of isocitrate dehydrogenase mutations influence clinical characteristics and disease outcome of acute myeloid leukemia. Leuk Lymphoma. 2013;54(5):1028–1035.
  • Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–344.
  • Schnittger S, Haferlach C, Ulke M, et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood. 2010;116(25):5486–5496.
  • Marcucci G, Maharry K, Wu YZ, et 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. 2010;28(14):2348–2355.
  • Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–744.
  • Ward PS, Patel J, Wise DR, 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(3):225–234.
  • Fathi AT, Abdel-Wahab O. Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy. Adv Hematol. 2012;2012:469592.
  • Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.
  • Rakheja D, Konoplev S, Medeiros LJ, et al. IDH mutations in acute myeloid leukemia. Hum Pathol. 2012;43(10):1541–1551.
  • Zhao S, Lin Y, Xu W, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science. 2009;324(5924):261–265.
  • Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–2068.
  • Röllig C, Müller-Tidow C, Hüttmann A, et al. Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial. Blood. 2014;124(21):6–6.
  • Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110–3118.
  • Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–4662.
  • Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681–3687.
  • Borthakur G, Kantarjian HM, O’Brien S, et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: Interim Report of a Phase I/II Trial. Blood. 2014;124(21):388–388.
  • Randhawa JK, Kantarjian HM, Borthakur G, et al. Results of a Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients (Pts) with Activating FLT3 Mutations. Blood. 2014;124(21):389–389.
  • Metzeler KH, Walker A, Geyer S, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012;26(5):1106–1107.
  • Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25(7):1147–1152.
  • Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774–1783.
  • Stein EM, Altman JK, Collins R, et al. AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies. Blood. 2014;124(21):115–115.
  • Medeiros BC, Majeti R. BCL-2 inhibition as a synthetic lethal approach to target isocitrate dehydrogenase mutations in acute myeloid leukemia stem cells. Blood. 2013;122(21):885–885.
  • Daigle SR, Olhava EJ, Therkelsen CA, et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013;122(6):1017–1025.
  • Didier C, Demur C, Grimal F, et al. Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype. Cancer Biol Ther. 2012;13(5):307–313.
  • Gaymes TJ, Mohamedali AM, Patterson M, et al. Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies. Haematologica. 2013;98(9):1397–1406.
  • Gaymes TJ, Shall S, MacPherson LJ, et al. Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes. Haematologica. 2009;94(5):638–646.
  • Horton TM, Jenkins G, Pati D, et al. Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity. Mol Cancer Ther. 2009;8(8):2232–2242.
  • Bryant HE, Petermann E, Schultz N, et al. PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. Embo J. 2009;28(17):2601–2615.
  • Berti M, Ray Chaudhuri A, Thangavel S, et al. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nature Structural & Molecular Biology. 2013;20(3):347–354.
  • Haince JF, McDonald D, Rodrigue A, et al. PARP1-dependent kinetics of recruitment of MRE11 and NBS1 proteins to multiple DNA damage sites. J Biol Chem. 2008;283(2):1197–1208.
  • Wray J, Williamson EA, Singh SB, et al. PARP1 is required for chromosomal translocations. Blood. 2013;121(21):4359–4365.
  • Soni A, Siemann M, Grabos M, et al. Requirement for Parp-1 and DNA ligases 1 or 3 but not of Xrcc1 in chromosomal translocation formation by backup end joining. Nucleic Acids Res. 2014;42(10):6380–6392.
  • Xie C, Drenberg C, Edwards H, et al. Panobinostat enhances cytarabine and daunorubicin sensitivities in AML cells through suppressing the expression of BRCA1, CHK1, and Rad51. PLoS One. 2013;8(11):e79106.
  • Petruccelli LA, Pettersson F, Del Rincon SV, et al. Expression of leukemia-associated fusion proteins increases sensitivity to histone deacetylase inhibitor-induced DNA damage and apoptosis. Mol Cancer Ther. 2013;12(8):1591–1604.
  • Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–1496.
  • Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121(24):4854–4860.
  • Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369–377.
  • Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508–1516.
  • Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2015;127(1):53–61. doi:10.1182/blood-2015-08-604520
  • Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986–996.
  • Damiani D, Tiribelli M, Raspadori D, et al. Clinical impact of CD200 expression in patients with acute myeloid leukemia and correlation with other molecular prognostic factors. Oncotarget. 2015;6(30):30212–30221. doi:10.18632/oncotarget.4901
  • Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478(7370):524–528.
  • Herrmann H, Blatt K, Shi J, et al. Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML. Oncotarget. 2012;3(12):1588–1599.
  • Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506-510.
  • Klco JM, Spencer DH, Miller CA, et al. Functional heterogeneity of genetically defined subclones in acute myeloid leukemia. Cancer Cell. 2014;25(3):379–392.

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