cytogenetic aberrations

Genetic Mutations in Acute Myeloid Leukemia

REVIEWS , , , , ,

OV Blau

Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

For correspondence: Ol’ga Vladimirovna Blau, DSci, Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Hindenburgdamm 30, 12200, Berlin, Germany; e-mail: olga.blau@charite.de.

For citation: Blau OV. Genetic Mutations in Acute Myeloid Leukemia. Clinical oncohematology. 2016;9(3):245-56 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-245-256

ABSTRACT

Acute myeloid leukemia (AML) is a clonal malignancy characterized by ineffective hematopoiesis. Most AML patients present different cytogenetic and molecular defects associated with certain biologic and clinical features of the disease. Approximately 50–60 % of de novo AML and 80–95 % of secondary AML patients demonstrate chromosomal aberrations. Structural chromosomal aberrations are the most common cytogenetic abnormalities in about of 40 % of de novo AML patients. A relatively large group of intermediate risk patients with cytogenetically normal (CN) AML demonstrates a variety of outcomes. Current AML prognostic classifications include only some mutations with known prognostic value, namely NPM1, FLT3 and C/EBPa. Patients with NPM1 mutation, but without FLT3-ITD or C/EBPa mutations have a favorable prognosis, whereas patients with FLT3-ITD mutation have a poor prognosis. A new class of mutations affecting genes responsible for epigenetic mechanisms of genome regulations, namely for DNA methylation and histone modification, was found recently. Among them, mutations in genes DNMT3A, IDH1/2, TET2 and some others are the most well-studied mutations to date. A number of studies demonstrated an unfavorable prognostic effect of the DNMT3A mutation in AML. The prognostic significance of the IDH1/2 gene is still unclear. The prognosis is affected by a number of biological factors, including those associated with cytogenetic aberrations and other mutations, especially FLT3 and NPM1. The number of studies of genetic mutations in AML keeps growing. The data on genetic aberrations in AML obtained to date confirm their role in the onset and development of the disease.

Keywords: acute myeloid leukemia, AML, karyotype, cytogenetic aberrations, gene mutation, prognosis.

Received: January 23, 2016

Accepted: April 4, 2016

Read in PDF (RUS)pdficon

REFERENCES

  1. Renneville A, Roumier С., Biggio V, et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22(5):915–31. doi: 10.1038/leu.2008.19.
  2. Knudson AG. Mutation and Cancer: Statistical Study of Retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820–3. doi: 10.1073/pnas.68.4.820.
  3. Tucker T, Friedman JM. Pathogenesis of hereditary tumors: beyond the “two-hit” hypothesis. Clin Genet. 2002;62(5):345–57. doi: 10.1034/j.1399-0004.2002.620501.x.
  4. Park S, Koh Y, Yoon SS. Effects of Somatic Mutations Are Associated with SNP in the Progression of Individual Acute Myeloid Leukemia Patient: The Two-Hit Theory Explains Inherited Predisposition to Pathogenesis. Genom Inform. 2013;11(1):34–7. doi: 10.5808/gi.2013.11.1.34.
  5. Genovese G, Kahler AK, Handsaker RE, et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. N Engl J Med. 2014;371(26):2477–87. doi: 10.1056/nejmoa1409405.
  6. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11. doi: 10.1038/35102167.
  7. Grimwade D. The changing paradigm of prognostic factors in acute myeloid leukaemia. Best Pract Res Clin Haematol. 2012;25(4):419–25. 10.1016/j.beha.2012.10.004.
  8. 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):1079–89. doi: 10.1056/nejmoa1112304.
  9. 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):453–74. doi: 10.1182/blood-2009-07-235358.
  10. Frehlick LJ, Eirin-Lopez JM, Ausio J. New insights into the nucleophosmin/nucleoplasmin family of nuclear chaperones. Bioessays. 2007;29(1):49–59. doi: 10.1002/bies.20512.
  11. Kurki S, Peltonen K, Latonen L, et al. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cell. 2004;5(5):465–75. doi: 10.1016/s1535-6108(04)00110-2.
  12. Lindstrom MS. NPM1/B23: A Multifunctional Chaperone in Ribosome Biogenesis and Chromatin Remodeling. Biochem Res Int. 2011;2011:1–16. doi: 10.1155/2011/195209.
  13. Falini B, Bolli NI, Martelli MP, et al. Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. 2007;92(4):519–32. doi: 10.3324/haematol.11007.
  14. Falini B, Bigerna B, Pucciarini A, et al. Aberrant subcellular expression of nucleophosmin and NPM-MLF1 fusion protein in acute myeloid leukaemia carrying t(3;5): a comparison with NPMc+ AML. Leukemia. 2006;20(2):368–71. doi: 10.1038/sj.leu.2404068.
  15. Redner R, Rush EA, Faas S, et al. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. 1996;87(3):882–6.
  16. Sportoletti P, Varasano E, Rossi R, et al. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications. 2015;29(2):269–78. doi: 10.1038/leu.2014.257.
  17. Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6(7):493–505. doi: 10.1038/nrc1885.
  18. Sportoletti P, Grisendi S, Majid SM, et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood; 2008;111(7):3859–62. doi: 10.1182/blood-2007-06-098251.
  19. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. The Lancet. 2013;381(9865):484–95. doi: 10.1016/s0140-6736(12)61727-9.
  20. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic Nucleophosmin in Acute Myelogenous Leukemia with a Normal Karyotype. N Engl J Med. 2005;352(3):254–66. doi: 10.1056/nejmoa041974.
  21. Falini B, Martelli MP, Pileri SA, Mecucci C. Molecular and alternative methods for diagnosis of acute myeloid leukemia with mutated NPM1: flexibility may help. 2010;95(4):529–34. doi: 10.3324/haematol.2009.017822.
  22. Falini B, Albiero E, Bolli N, et al. Aberrant cytoplasmic expression of C-terminal-truncated NPM leukaemic mutant is dictated by tryptophans loss and a new NES motif. Leukemia. 2007;21(9):2052–4. doi: 10.1038/sj.leu.2404839.
  23. 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):1909–18. doi: 10.1056/nejmoa074306.
  24. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication. J Clin Oncol. 2010. 28(22):3636–43. doi: 10.1200/jco.2010.28.3762.
  25. Dvorakova D, Racil Z, Jeziskova I, et al. Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient-specific NPM1 mutations. Am J Hematol. 2010;85(12):926–9. doi: 10.1002/ajh.21879.
  26. Schnittger S, Kern W, Tschulik C, et al. Minimal residual disease levels assessed by NPM1 mutation–specific RQ-PCR provide important prognostic information in AML. Blood. 2009;114(11):2220–31. doi: 10.1182/blood-2009-03-213389.
  27. Stahl T, Badbaran A, Kroger N, et al. Minimal residual disease diagnostics in patients with acute myeloid leukemia in the post-transplant period: comparison of peripheral blood and bone marrow analysis. Leuk Lymphoma. 2010;51(10):1837–43. doi: 10.3109/10428194.2010.508822.
  28. Kronke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29(19):2709–16. doi: 10.1200/jco.2011.35.0371.
  29. Rosnet O, Schiff C, Pebusque MJ, et al. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood. 1993;82(4):1110–9.
  30. Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15(13):4263–9. doi: 10.1158/1078-0432.ccr-08-1123.
  31. Sitnicka E, Buza-Vidas N, Larsson S, et al. Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3: distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells. Blood. 2003;102(3):881–6. doi: 10.1182/blood-2002-06-1694.
  32. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100(5):1532–42. doi: 10.1182/blood-2002-02-0492.
  33. Adolfsson J, Borge OJ, Bryder D, et al. Upregulation of Flt3 Expression within the Bone Marrow Lin–Sca1+c-kit+ Stem Cell Compartment Is Accompanied by Loss of Self-Renewal Capacity. Immunity. 2001;15(4):659–69. doi: 10.1016/s1074-7613(01)00220-5.
  34. Griffith J, Black J, Faerman C, et al. The Structural Basis for Autoinhibition of FLT3 by the Juxtamembrane Domain. Mol Cell. 2004;13(2):169–78. doi: 10.1016/s1097-2765(03)00505-7.
  35. 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):2776–84. doi: 10.1182/blood-2007-08-109090.
  36. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9. doi: 10.1182/blood.v98.6.1752.
  37. Marcucci G, Haferlach T, Dohner H. Molecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications. J Clin Oncol. 2011;29(5):475–86. doi: 10.1200/jco.2010.30.2554.
  38. Schnittger S, Schoch C, Dugas M, et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. 2002;100(1):59–66. doi: 10.1182/blood.v100.1.59.
  39. Breitenbuecher F, Schnittger S, Grundler R, et al. Identification of a novel type of ITD mutations located in nonjuxtamembrane domains of the FLT3 tyrosine kinase receptor. Blood. 2009;113:4074–7. doi: 10.1182/blood-2007-11-125476.
  40. Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114(12):2386–92. doi: 10.1182/blood-2009-03-209999.
  41. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD–positive AML with respect to allogeneic transplantation. Blood. 2014;124(23):3441–9. doi: 10.1182/blood-2014-05-578070.
  42. Gu TL, Nardone J, Wang Y, et al. Survey of Activated FLT3 Signaling in Leukemia. PLoS One, 2011;6(4):e19169. doi: 10.1371/journal.pone.0019169.
  43. Rocnik JL, Okabe R, Yu JC, et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood. 2006;108(4):1339–45. doi: 10.1182/blood-2005-11-011429.
  44. Blau O, Berenstein R, Sindram A, Blau IW. Molecular analysis of different FLT3-ITD mutations in acute myeloid leukemia. Leuk Lymphoma. 2013;54(1):145–52. doi: 10.3109/10428194.2012.704999.
  45. Frohling S, Schlenk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372–80. doi: 10.1182/blood-2002-05-1440.
  46. Mrozek K, Marcucci G, Paschka P, et al. 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):431–48. doi: 10.1182/blood-2006-06-001149.
  47. Sengsayadeth SM, Jagasia M, Engelhardt BG, et al. Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers. Bone Marrow Transplant. 2012;47(12):1535–7. doi: 10.1038/bmt.2012.88.
  48. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434–9. doi: 10.1182/blood.v97.8.2434.
  49. Mead AJ, Linch DC, Hills RK, et al. FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood. 2007;110(4):1262–70. doi: 10.1182/blood-2006-04-015826.
  50. Whitman SP, Ruppert AS, Radmacher MD, et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood. 2008;111(3):1552–9. doi: 10.1182/blood-2007-08-107946.
  51. Ozeki K, Kiyoi H, Hirose Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103(5):1901–8. doi: 10.1182/blood-2003-06-1845.
  52. Ley TJ, Miller C, Ding L, et al. Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia. N Engl J Med. 2013;368(22):2059–74. doi: 10.1056/nejmoa1301689.
  53. Gaidzik VI, Schlenk RF, Paschka P, et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood. 2013;121(23):4769–77. doi: 10.1182/blood-2012-10-461624.
  54. Kottaridis PD, Gale RE, Langabeer SE, et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood. 2002;100(7):2393–8. doi: 10.1182/blood-2002-02-0420.
  55. Shih LY, Huang CF, Wu JH, et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood. 2002;100(7):2387–92. doi: 10.1182/blood-2002-01-0195.
  56. Chu SH, Small D. Mechanisms of resistance to FLT3 inhibitors. Drug Resist Update. 2009;12(1–2):8–16. doi: 10.1016/j.drup.2008.12.001.
  57. 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):1462–70. doi: 10.1038/leu.2012.52.
  58. Mead AJ, Gale RE, Kottaridis PD, et al. Acute myeloid leukaemia blast cells with a tyrosine kinase domain mutation of FLT3 are less sensitive to lestaurtinib than those with a FLT3 internal tandem duplication. Br J Haematol. 2008;141(4):454–60. doi: 10.1111/j.1365-2141.2008.07025.x.
  59. Koschmieder S, Halmos B, Levantini E, Tenen DG. Dysregulation of the C/EBPa Differentiation Pathway in Human Cancer. J Clin Oncol. 2009;27(4):619–28. doi: 10.1200/jco.2008.17.9812.
  60. Wang H, Iakova P, Wilde M, et al. C/EBPa Arrests Cell Proliferation through Direct Inhibition of Cdk2 and Cdk4. Mol Cell. 2001;8(4):817–28. doi: 10.1016/s1097-2765(01)00366-5.
  61. Radomska HS, Huettner CS, Zhang P, et al. CCAAT enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998;18(7):4301–14. doi: 10.1128/mcb.18.7.4301.
  62. Zhang DE, Zhang P, Wang ND, et al. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein a-deficient mice. Proc Natl Acad Sci USA. 1997;94(2):569–74. doi: 10.1073/pnas.94.2.569.
  63. Umek RM, Friedman AD, McKnight SL. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991;251(4991):288–92. doi: 10.1126/science.1987644.
  64. Watkins PJ, Condreay JP, Huber BE, et al. Proliferation and tumorigenicity induced by CCAAT/enhancer-binding protein. Cancer Res. 1996;56(5):1063–7.
  65. Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-[alpha] (C/EBP [alpha]), in acute myeloid leukemia. Nat Genet. 2001;27(3):263–70. doi: 10.1038/85820.
  66. Nerlov C. C/EBP [alpha] mutations in acute myeloid leukaemias. Nat Rev Cancer. 2004;4(5):394–400. doi: 10.1038/nrc1363.
  67. Wouters BJ, Jorda MA, Keeshan K, et. al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood. 2007;110(10):3706–14. doi: 10.1182/blood-2007-02-073486.
  68. Taskesen E, Bullinger L, Corbacioglu A, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117(8):2469–75. doi: 10.1182/blood-2010-09-307280.
  69. Kirstetter P, Schuster MB, Bereshchenko O, et al. Modeling of C/EBPa Mutant Acute Myeloid Leukemia Reveals a Common Expression Signature of Committed Myeloid Leukemia-Initiating Cells. Cancer Cell. 2008;13(4):299–310. doi: 10.1016/j.ccr.2008.02.008.
  70. Shih LY, Liang DC, Huang CF, et al. AML patients with CEBP [alpha] mutations mostly retain identical mutant patterns but frequently change in allelic distribution at relapse: a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2006;20(4):604–9. doi: 10.1038/sj.leu.2404124.
  71. 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):3088–91. doi: 10.1182/blood-2008-09-179895.
  72. Cagnetta A, Adamia S, Acharya C, et al. Role of genotype-based approach in the clinical management of adult acute myeloid leukemia with normal cytogenetics. Leuk Res. 2014;38(6):649–59. doi: 10.1016/j.leukres.2014.03.006.
  73. Wouters BJ, Sanders MA, Lugthart S, et al. Segmental uniparental disomy as a recurrent mechanism for homozygous CEBPA mutations in acute myeloid leukemia. Leukemia. 2007;21(11):2382–4. doi: 10.1038/sj.leu.2404795.
  74. Valk PJM, Verhaak RG, Beijen MA, et al. Prognostically Useful Gene-Expression Profiles in Acute Myeloid Leukemia. N Engl J Med. 2004;350(16):1617–28. doi: 10.1056/nejmoa040465.
  75. Marceau-Renaut A, Guihard S, Castaigne S, et al. Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations. Am J Hematol. 2015;90(5):E93–4. doi: 10.1002/ajh.23949.
  76. Pabst T, Mueller BU. Transcriptional dysregulation during myeloid transformation in AML. Oncogene. 2007;26(47):6829–37. doi: 10.1038/sj.onc.1210765.
  77. Frohling S, Schlenk RF, Krauter J, et al. Acute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations. Genes Chromos Cancer. 2005;42(4):427–32. doi: 10.1002/gcc.20152.
  78. 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):2739–47. doi: 10.1200/jco.2009.26.2501.
  79. Behdad A, Weigelin HC, Elenitoba-Johnson KS, Betz BL. A Clinical Grade Sequencing-Based Assay for CEBPA Mutation Testing: Report of a Large Series of Myeloid Neoplasms. J Mol Diagn. 2015;17(1):76–84. doi: 10.1016/j.jmoldx.2014.09.007.
  80. Bienz M, Ludwig M, Leibundgut EO, et al. Risk Assessment in Patients with Acute Myeloid Leukemia and a Normal Karyotype. Clin Cancer Res. 2005;11(4):1416–24. doi: 10.1158/1078-0432.ccr-04-1552.
  81. 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):624–33. doi: 10.1200/jco.2004.06.060.
  82. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood. 2002;100(8):2717–23. doi: 10.1182/blood-2002-03-0990.
  83. Pastore F, Kling D, Hoster E, et al. Long-term follow-up of cytogenetically normal CEBPA-mutated AML. J Hematol Oncol. 2014;7(1):55. doi: 10.1186/s13045-014-0055-7.
  84. Park SH, Chi H-S, Cho Y-U, et al. CEBPA single mutation can be a possible favorable prognostic indicator in NPM1 and FLT3-ITD wild-type acute myeloid leukemia patients with intermediate cytogenetic risk. Leuk Res. 2013;37(11):1488–94. doi: 10.1016/j.leukres.2013.08.014.
  85. Renneville A, Boissel N, Gachard N, et al. The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication. Blood. 2009;113(21):5090–3. doi: 10.1182/blood-2008-12-194704.
  86. Taniuchi I, Littman DR. Epigenetic gene silencing by Runx proteins. Oncogene. 2004;23(24):4341–5. doi: 10.1038/sj.onc.1207671.
  87. Yoshida H, Kitabayashi I. Chromatin regulation by AML1 complex. Int J Hematol. 2008;87(1):19–24. doi: 10.1007/s12185-007-0004-0.
  88. 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. 2009;114(26):5352–61. doi: 10.1182/blood-2009-05-223784.
  89. Dicker F, Haferlach C, Sundermann J, et al. Mutation analysis for RUNX1, MLL-PTD, FLT3-ITD, NPM1 and NRAS in 269 patients with MDS or secondary AML. Leukemia. 2010;24(8):1528–32. doi: 10.1038/leu.2010.124.
  90. Gaidzik VI, Bullinger L, Schlenk RF, et al. RUNX1 Mutations in Acute Myeloid Leukemia: Results From a Comprehensive Genetic and Clinical Analysis From the AML Study Group. J Clin Oncol. 2011;29(10):1364–72. doi: 10.1200/jco.2010.30.7926.
  91. Dicker F, Haferlach C, Kern W, et al. Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood. 2007;110:1308–16. doi: 10.1182/blood-2007-02-072595.
  92. Matsuno N, Osato M, Yamashita N, et al. Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype. Leukemia. 2003;17(12):2492–9. doi: 10.1038/sj.leu.2403160.
  93. Mendler JH, Maharry K, Becker H, et al. In rare acute myeloid leukemia patients harboring both RUNX1 and NPM1 mutations, RUNX1 mutations are unusual in structure and present in the germline. 2013;98(8):e92–4. doi: 10.3324/haematol.2013.089904.
  94. Fasan A, Haferlach C, Kohlmann A, et al. Rare coincident NPM1 and RUNX1 mutations in intermediate risk acute myeloid leukemia display similar patterns to single mutated cases. Haematologica. 2014;99(2):e20–1. doi: 10.3324/haematol.2013.099754.
  95. Fernandez-Medarde A, Santos E. Ras in Cancer and Developmental Diseases. Genes Cancer. 2011;2(3):344–58. doi: 10.1177/1947601911411084.
  96. Stites EC, Ravichandran KS. A Systems Perspective of Ras Signaling in Cancer. Clin Cancer Res. 2009;15(5):1510–3. doi: 10.1158/1078-0432.ccr-08-2753.
  97. Johnson DB, Smalley KSM, Sosman JA. Molecular Pathways: Targeting NRAS in Melanoma and Acute Myelogenous Leukemia. Clin Cancer Res. 2014;20(16):4186–92. doi: 10.1158/1078-0432.ccr-13-3270.
  98. Fedorenko IV, Gibney GT, Smalley KSM. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013;32(25):3009–18. doi: 10.1038/onc.2012.
  99. Reuter CM, Krauter J, Onono FO, et al. Lack of noncanonical RAS mutations in cytogenetically normal acute myeloid leukemia. Ann Hematol. 2014;93(6):977–82. doi: 10.1007/s00277-014-2061-9.
  100. Bacher U, Haferlach T, Schoch C, et al. Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107(10):3847–53. doi: 10.1182/blood-2005-08-3522.
  101. Padua RA, West RR. Oncogene mutation and prognosis in the myelodysplastic syndromes. Br J Haematol. 2000;111(3):873–4. doi: 10.1111/j.1365-2141.2000.02472.x.
  102. Berman JN, Gerbing RB, Alonzo TA, et al. Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children’s Oncology Group. 2011;25(6):1039–42. doi: 10.1038/leu.2011.31.
  103. Bowen DT, Frew ME, Hills R, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood. 2005;106(6):2113–9. doi: 10.1182/blood-2005-03-0867.
  104. Roskoski R Jr. Structure and regulation of Kit protein-tyrosine kinase–The stem cell factor receptor. Biochem Biophys Res Commun. 2005;338(3):1307–15. doi: 10.1016/j.bbrc.2005.09.150.
  105. Yarden Y, Ullrich A. Growth Factor Receptor Tyrosine Kinases. Ann Rev Biochem. 1988:57(1):443–78. doi: 10.1146/annurev.bi.57.070188.002303.
  106. Paschka P, Marcucci G, Ruppert AS, et al. Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24(24):3904–11. doi: 10.1200/jco.2006.06.9500.
  107. Riera L, Marmont F, Toppino D, et al. Core binding factor acute myeloid leukaemia and c-KIT mutations. Oncol Rep. 2013;29(5):1867–72. doi: 10.3892/or.2013.2328.
  108. Cairoli R, Beghini A, Grillo G, et al. Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood. 2006;107(9):3463–8. doi: 10.1182/blood-2005-09-3640.
  109. Park SH, Chi HS, Min SK, et al. Prognostic impact of c-KIT mutations in core binding factor acute myeloid leukemia. Leuk Res. 2011;35(10):1376–83. doi: 10.1016/j.leukres.2011.06.003.
  110. Hoyos M, Nomdedeu JF, Esteve J, et al. Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease. Eur J Haematol. 2013;91(3):209–18. doi: 10.1111/ejh.12130.
  111. Schnittger S, Kohl TM, Haferlach T, et al. KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood. 2006;107(5):1791–9. doi: 10.1182/blood-2005-04-1466.
  112. Jiao B, Wu CF, Liang Y, et al. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia. 2009;23(9):1598–604. doi: 10.1038/leu.2009.104.
  113. Qin YZ, Zhu HH, Jiang Q, et al. Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: A comprehensive large-scale study from a single Chinese center. Leuk Res. 2014;38(12):1435–40. doi: 10.1016/j.leukres.2014.09.017.
  114. O’Donnell MR, Tallman MS, Abboud CN, et al. Acute Myeloid Leukemia, Version 2.2013. J Natl Compr Canc Netw. 2013;11(9):1047–55.
  115. Tokumasu M, Murata C, Shimada A, et al. Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial. Leukemia. 2015;29(12):2438–41. doi: 10.1038/leu.2015.121.
  116. Ito S, D’Alessio AC, Taranova OV, et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010;466(7310):1129–33. doi: 10.1038/nature09303.
  117. Chen Q, Chen Y, Bian C, et al. TET2 promotes histone O-GlcNAcylation during gene transcription. 2013;493(7433):561–4. doi: 10.1038/nature11742.
  118. Aslanyan M, Kroeze LI, Langemeijer SM, et al. Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial. Ann Hematol. 2014;93(8):1401–12. doi: 10.1007/s00277-014-2055-7.
  119. 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):3803–10. doi: 10.1182/blood-2011-02-339747.
  120. 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):1373–81. doi: 10.1200/jco.2010.32.7742.
  121. 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):1350–7. doi: 10.1200/jco.2011.39.2886.
  122. Ko M, Huang Y, Jankowska AM, et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. 2010;468(7325):839–43. doi: 10.1038/nature09586.
  123. 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):553–67. doi: 10.1016/j.ccr.2010.11.015.
  124. 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. doi: 10.1016/j.ccr.2011.06.001.
  125. Quivoron C, Couronne L, Della Valle V, et al. TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis. Cancer Cell. 2011;20(1):25–38. doi: 10.1016/j.ccr.2011.06.003.
  126. Nibourel O, Kosmider O, Cheok M, et al. Incidence and prognostic value of TET2 alterations in de novo acute myeloid leukemia achieving complete remission. Blood. 2010;116(7):1132–5. doi: 10.1182/blood-2009-07-234484.
  127. Weissmann S, Alpermann T, Grossmann V, et al. Landscape of TET2 mutations in acute myeloid leukemia. Leukemia. 2012;26(5):934–42. doi: 10.1038/leu.2011.326.
  128. Reitman ZJ, Yan H. Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism. J Natl Cancer Inst. 2010;102(13):932–41. doi: 10.1093/jnci/djq187.
  129. Molenaar RJ, Radivoyevitch T, Maciejewski JP, et al. The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation. Biochim Biophys Acta. 2014;1846(2):326–41. doi: 10.1016/j.bbcan.2014.05.004.
  130. Emadi A, Faramand R, Carter-Cooper B, et al. Presence of isocitrate dehydrogenase (IDH) mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia (AML). Am J Hematol. 2015;90(5):E77–9. doi: 10.1002/ajh.23965.
  131. Abbas S, Lugthart S, Kavelaars FG, et al. Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value. Blood. 2010;116(12):2122–6. doi: 10.1182/blood-2009-11-250878.
  132. 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):2348–55. doi: 10.1200/jco.2009.27.3730.
  133. Dang L, Jin S, Su SM. IDH mutations in glioma and acute myeloid leukemia. Trends Mol Med. 2010;16(9):387–97. doi: 10.1016/j.molmed.2010.07.002.
  134. Horbinski C. What do we know about IDH1/2 mutations so far, and how do we use it? Acta Neuropathol. 2013;125(5):621–36. doi: 10.1007/s00401-013-1106-9.
  135. Chotirat S, Thongnoppakhun W, Wanachiwanawin W, Auewarakul CU. Acquired somatic mutations of isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) in preleukemic disorders. Blood Cells Mol Dis. 2015;54(3):286–91. doi: 10.1016/j.bcmd.2014.11.017.
  136. 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):409–12. doi: 10.1182/blood-2010-12-322479.
  137. Zhou KG, Jiang LJ, Shang Z, et al. Potential application of IDH1 and IDH2 mutations as prognostic indicators in non-promyelocytic acute myeloid leukemia: a meta-analysis. Leuk Lymphoma. 2012;53(12):2423–9. doi: 10.3109/10428194.2012.695359.
  138. Marcucci G, Metzeler KH, Schwind S, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012;30(7):742–50. doi: 10.1200/jco.2011.39.2092.
  139. Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. doi: 10.1056/nejmoa1005143.
  140. Zhang Y, Chen FQ, Sun YH, et al. Effects of DNMT1 silencing on malignant phenotype and methylated gene expression in cervical cancer cells. J Exp Clin Cancer Res. 2011;30(1):98. doi: 10.1186/1756-9966-30-98.
  141. Jasielec J, Saloura V, Godley LA. The mechanistic role of DNA methylation in myeloid leukemogenesis. Leukemia. 2014;28(9):1765–73. doi: 10.1038/leu.2014.163.
  142. Li KK, Luo LF, Shen Y, et al. DNA methyltransferases in hematologic malignancies. Semin Hematol. 2013;50(1):48–60. doi: 10.1053/j.seminhematol.2013.01.005.
  143. O’Brien EC, Brewin J, Chevassut T. DNMT3A: the DioNysian MonsTer of acute myeloid leukaemia. Ther Adv Hematol. 2014;5(6):187–96. doi: 10.1177/2040620714554538.
  144. Holz-Schietinger C, Matje DM, Reich NO. Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. J Biol Chem. 2012;287(37):30941–51. doi: 10.1074/jbc.m112.366625.
  145. Russler-Germain DA, Spencer DH, Young MA, et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014;25(4):442–54. doi: 10.1016/j.ccr.2014.02.010146.
  146. McDevitt MA. Clinical applications of epigenetic markers and epigenetic profiling in myeloid malignancies. Semin Oncol. 2012;39(1):109–22. doi: 10.1053/j.seminoncol.2011.11.003.
  147. Berenstein R, Blau IW, Suckert N, et al. Quantitative detection of DNMT3A R882H mutation in acute myeloid leukemia. J Exp Clin Cancer Res. 2015;34(1):55. doi: 10.1186/s13046-015-0173-2.
  148. Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506(7488):328–33. doi: 10.1038/nature13038.
  149. Corces-Zimmerman MR, Hong WJ, Weissman IL, et al. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111(7):2548–53. doi: 10.1073/pnas.1324297111.
  150. Thol F, Damm F, Ludeking A, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21):2889–96. doi: 10.1200/jco.2011.35.4894.
  151. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012;119(24):5824–31. doi: 10.1182/blood-2011-07-367961.
  152. Ibrahem L, Mahfouz R, Elhelw L, et al. Prognostic significance of DNMT3A mutations in patients with acute myeloid leukemia. Blood Cells Mol Dis. 2014;54(1):84–9. doi: 10.1016/j.bcmd.2014.07.015.
  153. Shivarov V, Gueorguieva R, Stoimenov A, Tiu R. DNMT3A mutation is a poor prognosis biomarker in AML: results of a meta-analysis of 4500 AML patients. Leuk Res. 2013;37(11):1445–50. doi: 10.1016/j.leukres.2013.07.032.
  154. Wakita S, Yamaguchi H, Omori I, et al. Mutations of the epigenetics-modifying gene (DNMT3a, TET2, IDH1/2) at diagnosis may induce FLT3-ITD at relapse in de novo acute myeloid leukemia. Leukemia. 2013;27(5):1044–52. doi: 10.1038/leu.2012.317.
  155. Hou HA, Kuo YY, Liu CY, et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood. 2012;119(2):559–68. doi: 10.1182/blood-2011-07-369934.
  156. Ploen GG, Nederby L, Guldberg P, et al. Persistence of DNMT3A mutations at long-term remission in adult patients with AML. Br J Haematol. 2014;167(4):478–86. doi: 10.1111/bjh.13062.
  157. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98. doi: 10.1056/nejmoa1408617.