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Molecular-Based Classification of Acute Myeloid Leukemia and Its Role in Directing Rational Therapy

Personalized Medicine for Profoundly Promiscuous Proliferations

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Abstract

Acute myeloid leukemia (AML) is not a single pathologic entity but represents a heterogeneous group of malignancies. This heterogeneity is exemplified by the variable clinical outcomes that are observed in patients with AML, and it is largely the result of diverse mutations within the leukemic cells. These mutations range from relatively large genetic alterations, such as gains, losses, and translocations of chromosomes, to single nucleotide changes. Detection of many of these mutations is required for accurate diagnosis, prognosis, and treatment of patients with AML. As such, many testing modalities have been developed and are currently employed in clinical laboratories to ascertain mutational status at prognostically and therapeutically critical loci. The assays include those that specifically identify large chromosomal alterations, such as conventional metaphase analysis and fluorescence in situ hybridization, and methods that are geared more toward analysis of small mutations, such as PCR with allele-specific oligonucleotide primers. Furthermore, newer tests, including array analysis and next-generation sequencing, which can simultaneously probe numerous molecular aberrancies within tumor cells, are likely to become commonplace in AML diagnostics. Each testing method clearly has advantages and disadvantages, an understanding of which should influence the choice of test in various clinical circumstances. To aid such understanding, this review discusses both genetic mutations in AML and the clinical tests—including their pros and cons—that may be used to probe these abnormalities. Additionally, we highlight the significance of genetic testing by describing cases in which results of genetic testing significantly influence clinical management of patients with AML.

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References

  1. American Cancer Society. Cancer facts and figures 2011. Atlanta: American Cancer Society; 2011.

    Google Scholar 

  2. Pulte D, Gondos A, Brenner H. Expected long-term survival of patients diagnosed with acute myeloblastic leukemia during 2006–2010. Ann Oncol. 2010;21(2):335–41.

    Article  PubMed  CAS  Google Scholar 

  3. Gulley ML, Shea TC, Fedoriw Y. Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. J Mol Diagn. 2010;12(1):3–16.

    Article  PubMed  CAS  Google Scholar 

  4. Grimwade D, Mrozek K. Diagnostic and prognostic value of cytogenetics in acute myeloid leukemia. Hematol Oncol Clin North Am. 2011;25(6):1135–61, vii.

    Google Scholar 

  5. Watt CD, Bagg A. Molecular diagnosis of acute myeloid leukemia. Expert Rev Mol Diagn. 2010;10(8):993–1012.

    Article  PubMed  Google Scholar 

  6. Morrissette JJ, Bagg A. Acute myeloid leukemia: conventional cytogenetics, FISH, and moleculocentric methodologies. Clin Lab Med. 2011;31(4):659–86.

    Article  PubMed  Google Scholar 

  7. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2008.

    Google Scholar 

  8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: acute myeloid leukemia version 2.2012. Fort Washington: National Comprehensive Cancer Network; 2012.

  9. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2(7):502–13.

    Article  PubMed  CAS  Google Scholar 

  10. Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood. 2006;107(8):3330–8.

    Article  PubMed  CAS  Google Scholar 

  11. de Bruijn MF, Speck NA. Core-binding factors in hematopoiesis and immune function. Oncogene. 2004;23(24):4238–48.

    Article  PubMed  CAS  Google Scholar 

  12. Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW. The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol. 1998;18(1):322–33.

    PubMed  CAS  Google Scholar 

  13. Adya N, Stacy T, Speck NA, Liu PP. The leukemic protein core binding factor beta (CBFbeta)-smooth-muscle myosin heavy chain sequesters CBFalpha2 into cytoskeletal filaments and aggregates. Mol Cell Biol. 1998;18(12):7432–43.

    PubMed  CAS  Google Scholar 

  14. Labrecque J, Allan D, Chambon P, Iscove NN, Lohnes D, Hoang T. Impaired granulocytic differentiation in vitro in hematopoietic cells lacking retinoic acid receptors alpha1 and gamma. Blood. 1998;92(2):607–15.

    PubMed  CAS  Google Scholar 

  15. Purton LE, Dworkin S, Olsen GH, Walkley CR, Fabb SA, Collins SJ, et al. RARgamma is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J Exp Med. 2006;203(5):1283–93.

    Article  PubMed  CAS  Google Scholar 

  16. Ablain J, de The H. Revisiting the differentiation paradigm in acute promyelocytic leukemia. Blood. 2011;117(22):5795–802.

    Article  PubMed  CAS  Google Scholar 

  17. Walz C, Grimwade D, Saussele S, Lengfelder E, Haferlach C, Schnittger S, et al. Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia. Genes Chromosomes Cancer. 2010;49(5):471–9.

    PubMed  CAS  Google Scholar 

  18. Stein E, McMahon B, Kwaan H, Altman JK, Frankfurt O, Tallman MS. The coagulopathy of acute promyelocytic leukaemia revisited. Best Pract Res Clin Haematol. 2009;22(1):153–63.

    Article  PubMed  CAS  Google Scholar 

  19. Sanz MA, Montesinos P, Rayon C, Holowiecka A, de la Serna J, Milone G, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010;115(25):5137–46.

    Article  PubMed  CAS  Google Scholar 

  20. Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, et al. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 2008;10(5):547–55.

    Article  PubMed  CAS  Google Scholar 

  21. Chi Y, Lindgren V, Quigley S, Gaitonde S. Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia: an overview. Arch Pathol Lab Med. 2008;132(11):1835–7.

    PubMed  Google Scholar 

  22. Oancea C, Ruster B, Henschler R, Puccetti E, Ruthardt M. The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation. Leukemia. 2010;24(11):1910–9.

    Article  PubMed  CAS  Google Scholar 

  23. Lugthart S, Groschel S, Beverloo HB, Kayser S, Valk PJ, van Zelderen-Bhola SL, et al. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol. 2010;28(24):3890–8.

    Article  PubMed  Google Scholar 

  24. Groschel S, Lugthart S, Schlenk RF, Valk PJ, Eiwen K, Goudswaard C, et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities. J Clin Oncol. 2010;28(12):2101–7.

    Article  PubMed  CAS  Google Scholar 

  25. Lugthart S, van Drunen E, van Norden Y, van Hoven A, Erpelinck CA, Valk PJ, 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):4329–37.

    Article  PubMed  CAS  Google Scholar 

  26. Breems DA, Van Putten WL, De Greef GE, Van Zelderen-Bhola SL, Gerssen-Schoorl KB, Mellink CH, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26(29):4791–7.

    Article  PubMed  Google Scholar 

  27. Kayser S, Zucknick M, Dohner K, Krauter J, Kohne CH, Horst HA, et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood. 2012;119(2):551–8.

    Article  PubMed  CAS  Google Scholar 

  28. Medeiros BC, Othus M, Fang M, Roulston D, Appelbaum FR. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience. Blood. 2010;116(13):2224–8.

    Article  PubMed  CAS  Google Scholar 

  29. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007;7(11):823–33.

    Article  PubMed  CAS  Google Scholar 

  30. Coenen EA, Zwaan CM, Meyer C, Marschalek R, Pieters R, van der Veken LT, et al. KIAA1524: a novel MLL translocation partner in acute myeloid leukemia. Leuk Res. 2011;35(1):133–5.

    Article  PubMed  CAS  Google Scholar 

  31. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, 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):354–65.

    Article  PubMed  CAS  Google Scholar 

  32. Lion T, Haas OA, Harbott J, Bannier E, Ritterbach J, Jankovic M, et al. The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. Blood. 1992;79(12):3325–30.

    PubMed  CAS  Google Scholar 

  33. Hama A, Yagasaki H, Takahashi Y, Nishio N, Muramatsu H, Yoshida N, et al. Acute megakaryoblastic leukaemia (AMKL) in children: a comparison of AMKL with and without Down syndrome. Br J Haematol. 2008;140(5):552–61.

    Article  PubMed  Google Scholar 

  34. Wolff DJ, Bagg A, Cooley LD, Dewald GW, Hirsch BA, Jacky PB, et al. Guidance for fluorescence in situ hybridization testing in hematologic disorders. J Mol Diagn. 2007;9(2):134–43.

    Article  PubMed  CAS  Google Scholar 

  35. Frohling S, Skelin S, Liebisch C, Scholl C, Schlenk RF, Dohner H, et al. Comparison of cytogenetic and molecular cytogenetic detection of chromosome abnormalities in 240 consecutive adult patients with acute myeloid leukemia. J Clin Oncol. 2002;20(10):2480–5.

    Article  PubMed  CAS  Google Scholar 

  36. King RL, Naghashpour M, Watt CD, Morrissette JJ, Bagg A. A comparative analysis of molecular genetic and conventional cytogenetic detection of diagnostically important translocations in more than 400 cases of acute leukemia, highlighting the frequency of false-negative conventional cytogenetics. Am J Clin Pathol. 2011;135(6):921–8.

    Article  PubMed  Google Scholar 

  37. Frohling S, Kayser S, Mayer C, Miller S, Wieland C, Skelin S, et al. Diagnostic value of fluorescence in situ hybridization for the detection of genomic aberrations in older patients with acute myeloid leukemia. Haematologica. 2005;90(2):194–9.

    PubMed  Google Scholar 

  38. Zhao L, van Oort J, Cork A, Liang JC. Comparison between interphase and metaphase cytogenetics in detecting chromosome 7 defects in hematological neoplasias. Am J Hematol. 1993;43(3):205–11.

    Article  PubMed  CAS  Google Scholar 

  39. Zordan A. Fluorescence in situ hybridization on formalin-fixed, paraffin-embedded tissue sections. Methods Mol Biol. 2011;730:189–202.

    Article  PubMed  CAS  Google Scholar 

  40. Mancini M, Cedrone M, Diverio D, Emanuel B, Stul M, Vranckx H, et al. Use of dual-color interphase FISH for the detection of inv(16) in acute myeloid leukemia at diagnosis, relapse and during follow-up: a study of 23 patients. Leukemia. 2000;14(3):364–8.

    Article  PubMed  CAS  Google Scholar 

  41. Bacher U, Schnittger S, Haferlach C, Haferlach T. Molecular diagnostics in acute leukemias. Clin Chem Lab Med. 2009;47(11):1333–41.

    Article  PubMed  CAS  Google Scholar 

  42. Gallagher RE, Yeap BY, Bi W, Livak KJ, Beaubier N, Rao S, et al. Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129. Blood. 2003;101(7):2521–8.

    Article  PubMed  CAS  Google Scholar 

  43. Marcucci G, Caligiuri MA, Dohner H, Archer KJ, Schlenk RF, Dohner K, et al. Quantification of CBFbeta/MYH11 fusion transcript by real time RT-PCR in patients with INV(16) acute myeloid leukemia. Leukemia. 2001;15(7):1072–80.

    Article  PubMed  CAS  Google Scholar 

  44. Kusec R, Laczika K, Knobl P, Friedl J, Greinix H, Kahls P, et al. AML1/ETO fusion mRNA can be detected in remission blood samples of all patients with t(8;21) acute myeloid leukemia after chemotherapy or autologous bone marrow transplantation. Leukemia. 1994;8(5):735–9.

    PubMed  CAS  Google Scholar 

  45. Miyamoto T, Weissman IL, Akashi K. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. Proc Natl Acad Sci USA. 2000;97(13):7521–6.

    Article  PubMed  CAS  Google Scholar 

  46. Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood. 2002;99(10):3801–5.

    Article  PubMed  CAS  Google Scholar 

  47. Basecke J, Cepek L, Mannhalter C, Krauter J, Hildenhagen S, Brittinger G, et al. Transcription of AML1/ETO in bone marrow and cord blood of individuals without acute myelogenous leukemia. Blood. 2002;100(6):2267–8.

    Article  PubMed  CAS  Google Scholar 

  48. Song J, Mercer D, Hu X, Liu H, Li MM. Common leukemia- and lymphoma-associated genetic aberrations in healthy individuals. J Mol Diagn. 2011;13(2):213–9.

    Article  PubMed  CAS  Google Scholar 

  49. Jurlander J, Caligiuri MA, Ruutu T, Baer MR, Strout MP, Oberkircher AR, et al. Persistence of the AML1/ETO fusion transcript in patients treated with allogeneic bone marrow transplantation for t(8;21) leukemia. Blood. 1996;88(6):2183–91.

    PubMed  CAS  Google Scholar 

  50. Miyamoto T, Nagafuji K, Akashi K, Harada M, Kyo T, Akashi T, et al. Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. Blood. 1996;87(11):4789–96.

    PubMed  CAS  Google Scholar 

  51. Bullinger L, Kronke J, Schon C, Radtke I, Urlbauer K, Botzenhardt U, et al. Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis. Leukemia. 2010;24(2):438–49.

    Article  PubMed  CAS  Google Scholar 

  52. Yasar D, Karadogan I, Alanoglu G, Akkaya B, Luleci G, Salim O, et al. Array comparative genomic hybridization analysis of adult acute leukemia patients. Cancer Genet Cytogenet. 2010;197(2):122–9.

    Article  PubMed  CAS  Google Scholar 

  53. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Masse A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301.

    Article  PubMed  Google Scholar 

  54. King-Underwood L, Pritchard-Jones K. Wilms’ tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood. 1998;91(8):2961–8.

    PubMed  CAS  Google Scholar 

  55. Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Kronke J, Bullinger L, 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.

    Article  PubMed  CAS  Google Scholar 

  56. Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89.

    Article  PubMed  CAS  Google Scholar 

  57. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S, 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.

    Article  PubMed  CAS  Google Scholar 

  58. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M, et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer. 2010;10:401.

    Article  PubMed  CAS  Google Scholar 

  59. Rombouts WJ, Blokland I, Lowenberg B, Ploemacher RE. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the Flt3 gene. Leukemia. 2000;14(4):675–83.

    Article  PubMed  CAS  Google Scholar 

  60. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, et al. PHF6 mutations in adult acute myeloid leukemia. Leukemia. 2012;25(1):130–4.

    Google Scholar 

  61. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF, et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106(12):3733–9.

    Article  PubMed  CAS  Google Scholar 

  62. Thiede C, Koch S, Creutzig E, Steudel C, Illmer T, Schaich M, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107(10):4011–20.

    Article  PubMed  CAS  Google Scholar 

  63. Grisendi S, Mecucci C, Falini B, Pandolfi PP. Nucleophosmin and cancer. Nat Rev Cancer. 2006;6(7):493–505.

    Article  PubMed  CAS  Google Scholar 

  64. Meani N, Alcalay M. Role of nucleophosmin in acute myeloid leukemia. Expert Rev Anticancer Ther. 2009;9(9):1283–94.

    Article  PubMed  CAS  Google Scholar 

  65. Rau R, Brown P. Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity. Hematol Oncol. 2009;27(4):171–81.

    Article  PubMed  CAS  Google Scholar 

  66. Falini B, Mecucci C, Tiacci E, Alcalay M, Rosati R, Pasqualucci L, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254–66.

    Article  PubMed  CAS  Google Scholar 

  67. Wertheim G, Bagg A. Nucleophosmin (NPM1) mutations in acute myeloid leukemia: an ongoing (cytoplasmic) tale of dueling mutations and duality of molecular genetic testing methodologies. J Mol Diagn. 2008;10(3):198–202.

    Article  PubMed  CAS  Google Scholar 

  68. Luger SM. Treating the elderly patient with acute myelogenous leukemia. Hematol Am Soc Hematol Educ Program. 2010;2010:62–9.

    Article  Google Scholar 

  69. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci USA. 1997;94(2):569–74.

    Article  PubMed  CAS  Google Scholar 

  70. Helbling D, Mueller BU, Timchenko NA, Schardt J, Eyer M, Betts DR, et al. CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood. 2005;106(4):1369–75.

    Article  PubMed  CAS  Google Scholar 

  71. Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001;7(4):444–51.

    Article  PubMed  CAS  Google Scholar 

  72. Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(1):89–99.

    Article  PubMed  Google Scholar 

  73. Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E, 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):570–7.

    Article  PubMed  CAS  Google Scholar 

  74. Fos J, Pabst T, Petkovic V, Ratschiller D, Mueller BU. Deficient CEBPA DNA binding function in normal karyotype AML patients is associated with favorable prognosis. Blood. 2011;117(18):4881–4.

    Article  PubMed  CAS  Google Scholar 

  75. Paz-Priel I, Friedman A. C/EBPalpha dysregulation in AML and ALL. Crit Rev Oncog. 2011;16(1–2):93–102.

    Article  PubMed  Google Scholar 

  76. Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity. 1995;3(1):147–61.

    Article  PubMed  CAS  Google Scholar 

  77. Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J, 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.

    Article  PubMed  CAS  Google Scholar 

  78. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97(8):2434–9.

    Article  PubMed  CAS  Google Scholar 

  79. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK, 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.

    Article  PubMed  CAS  Google Scholar 

  80. Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res. 2009;15(13):4263–9.

    Article  PubMed  CAS  Google Scholar 

  81. Warren M, Luthra R, Yin CC, Ravandi F, Cortes JE, Kantarjian HM, et al. Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients. Mod Pathol. 2012;25(10):1405–12.

    Article  PubMed  CAS  Google Scholar 

  82. Swords R, Freeman C, Giles F. Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia. Leukemia. 2012;26(10):2176–85.

    Article  PubMed  CAS  Google Scholar 

  83. Levis M, Ravandi F, Wang ES, Baer MR, Perl A, Coutre S, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2011;117(12):3294–301.

    Article  PubMed  CAS  Google Scholar 

  84. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33.

    Article  PubMed  CAS  Google Scholar 

  85. Markova J, Michkova P, Burckova K, Brezinova J, Michalova K, Dohnalova A, et al. Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia. Eur J Haematol. 2012;88(2):128–35.

    Article  PubMed  CAS  Google Scholar 

  86. Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, Rockova V, Sanders M, Abbas S, et al. Mutant DNMT3A: a marker of poor prognosis in acute myeloid leukemia. Blood. 2012;119(24):5824–31.

    Article  PubMed  CAS  Google Scholar 

  87. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet. 2002;3(9):662–73.

    Article  PubMed  CAS  Google Scholar 

  88. Zhao Q, Zhang Y. Epigenome sequencing comes of age in development, differentiation and disease mechanism research. Epigenomics. 2011;3(2):207–20.

    Article  PubMed  CAS  Google Scholar 

  89. Thol F, Damm F, Ludeking A, Winschel C, Wagner K, Morgan M, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29(21):2889–96.

    Article  PubMed  CAS  Google Scholar 

  90. Ottone T, Ammatuna E, Lavorgna S, Noguera NI, Buccisano F, Venditti A, et al. An allele-specific rt-PCR assay to detect type A mutation of the nucleophosmin-1 gene in acute myeloid leukemia. J Mol Diagn. 2008;10(3):212–6.

    Article  PubMed  CAS  Google Scholar 

  91. Tsiatis AC, Norris-Kirby A, Rich RG, Hafez MJ, Gocke CD, Eshleman JR, et al. Comparison of Sanger sequencing, pyrosequencing, and melting curve analysis for the detection of KRAS mutations: diagnostic and clinical implications. J Mol Diagn. 2010;12(4):425–32.

    Article  PubMed  CAS  Google Scholar 

  92. Szankasi P, Jama M, Bahler DW. A new DNA-based test for detection of nucleophosmin exon 12 mutations by capillary electrophoresis. J Mol Diagn. 2008;10(3):236–41.

    Article  PubMed  CAS  Google Scholar 

  93. Hafez M, Ye F, Jackson K, Yang Z, Karp JE, Labourier E, et al. Performance and clinical evaluation of a sensitive multiplex assay for the rapid detection of common NPM1 mutations. J Mol Diagn. 2010;12(5):629–35.

    Article  PubMed  CAS  Google Scholar 

  94. Tan AY, Westerman DA, Carney DA, Seymour JF, Juneja S, Dobrovic A. Detection of NPM1 exon 12 mutations and FLT3—internal tandem duplications by high resolution melting analysis in normal karyotype acute myeloid leukemia. J Hematol Oncol. 2008;1:10.

    Article  PubMed  CAS  Google Scholar 

  95. Oelschlaegel U, Koch S, Mohr B, Schaich M, Falini B, Ehninger G, et al. Rapid flow cytometric detection of aberrant cytoplasmic localization of nucleophosmin (NPMc) indicating mutant NPM1 gene in acute myeloid leukemia. Leukemia. 2010;24(10):1813–6.

    Article  PubMed  CAS  Google Scholar 

  96. Chang TL, Salto-Tellez M, Kueh YK, Koay ES, et al. Simplified capillary electrophoresis detection of the Flt-3 internal tandem duplications and D835 point mutations in acute myeloid leukemia. Haematologica. 2003;88(2):ELT04.

    PubMed  Google Scholar 

  97. Murphy KM, Levis M, Hafez MJ, Geiger T, Cooper LC, Smith BD, et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn. 2003;5(2):96–102.

    Article  PubMed  CAS  Google Scholar 

  98. Lin TC, Jiang SS, Chou WC, Hou HA, Lin YM, Chang CL, et al. Rapid assessment of the heterogeneous methylation status of CEBPA in patients with acute myeloid leukemia by using high-resolution melting profile. J Mol Diagn. 2011;13(5):514–9.

    Article  PubMed  CAS  Google Scholar 

  99. Patel KP, Barkoh BA, Chen Z, Ma D, Reddy N, Medeiros LJ, et al. Diagnostic testing for IDH1 and IDH2 variants in acute myeloid leukemia: an algorithmic approach using high-resolution melting curve analysis. J Mol Diagn. 2011;13(6):678–86.

    Article  PubMed  CAS  Google Scholar 

  100. Vaughn CP, Elenitoba-Johnson KS. High-resolution melting analysis for detection of internal tandem duplications. J Mol Diagn. 2004;6(3):211–6.

    Article  PubMed  CAS  Google Scholar 

  101. Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E, et al. High levels of Wilms’ tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood. 1997;90(3):1217–25.

    PubMed  CAS  Google Scholar 

  102. Cristobal I, Blanco FJ, Garcia-Orti L, Marcotegui N, Vicente C, Rifon J, et al. SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. Blood. 2010;115(3):615–25.

    Article  PubMed  CAS  Google Scholar 

  103. Kornblau SM, Qiu YH, Zhang N, Singh N, Faderl S, Ferrajoli A, et al. Abnormal expression of FLI1 protein is an adverse prognostic factor in acute myeloid leukemia. Blood. 2011;118(20):5604–12.

    Article  PubMed  CAS  Google Scholar 

  104. Langer C, Marcucci G, Holland KB, Radmacher MD, Maharry K, Paschka P, et al. Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol. 2009;27(19):3198–204.

    Article  PubMed  CAS  Google Scholar 

  105. Santamaria CM, Chillon MC, Garcia-Sanz R, Perez C, Caballero MD, Ramos F, et al. High FOXO3a expression is associated with a poorer prognosis in AML with normal cytogenetics. Leuk Res. 2009;33(12):1706–9.

    Article  PubMed  CAS  Google Scholar 

  106. Schwind S, Marcucci G, Maharry K, Radmacher MD, Mrozek K, Holland KB, et al. BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. 2010;116(25):5660–9.

    Article  PubMed  CAS  Google Scholar 

  107. Metzeler KH, Hummel M, Bloomfield CD, Spiekermann K, Braess J, Sauerland MC, et al. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood. 2008;112(10):4193–201.

    Article  PubMed  CAS  Google Scholar 

  108. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med. 2004;350(16):1617–28.

    Article  PubMed  CAS  Google Scholar 

  109. Wilson CS, Davidson GS, Martin SB, Andries E, Potter J, Harvey R, et al. Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. Blood. 2006;108(2):685–96.

    Article  PubMed  CAS  Google Scholar 

  110. Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, et al. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood. 2008;111(6):3183–9.

    Article  PubMed  CAS  Google Scholar 

  111. Marcucci G, Mrozek K, Radmacher MD, Bloomfield CD, Croce CM. MicroRNA expression profiling in acute myeloid and chronic lymphocytic leukaemias. Best Pract Res Clin Haematol. 2009;22(2):239–48.

    Article  PubMed  CAS  Google Scholar 

  112. Schwind S, Maharry K, Radmacher MD, Mrozek K, Holland KB, Margeson D, et al. Prognostic significance of expression of a single microRNA, miR-181a, in cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28(36):5257–64.

    Article  PubMed  CAS  Google Scholar 

  113. Zhang H, Luo XQ, Feng DD, Zhang XJ, Wu J, Zheng YS, et al. Upregulation of microRNA-125b contributes to leukemogenesis and increases drug resistance in pediatric acute promyelocytic leukemia. Mol Cancer. 2011;10:108.

    Article  PubMed  CAS  Google Scholar 

  114. Baylin SB, Jones PA. A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer. 2011;11(10):726–34.

    Article  PubMed  CAS  Google Scholar 

  115. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, 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.

    Article  PubMed  CAS  Google Scholar 

  116. Hajkova H, Markova J, Haskovec C, Sarova I, Fuchs O, Kostecka A, et al. Decreased DNA methylation in acute myeloid leukemia patients with DNMT3A mutations and prognostic implications of DNA methylation. Leuk Res. 2012;36(9):1128–33.

    Article  PubMed  CAS  Google Scholar 

  117. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia. 2003;17(9):1813–9.

    Article  PubMed  CAS  Google Scholar 

  118. Hess CJ, Errami A, Berkhof J, Denkers F, Ossenkoppele GJ, Nygren AO, et al. Concurrent methylation of promoters from tumor associated genes predicts outcome in acute myeloid leukemia. Leuk Lymphoma. 2008;49(6):1132–41.

    Article  PubMed  CAS  Google Scholar 

  119. Shimamoto T, Ohyashiki JH, Ohyashiki K. Methylation of p15(INK4b) and E-cadherin genes is independently correlated with poor prognosis in acute myeloid leukemia. Leuk Res. 2005;29(6):653–9.

    Article  PubMed  CAS  Google Scholar 

  120. Alvarez S, Suela J, Valencia A, Fernandez A, Wunderlich M, Agirre X, et al. DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia. PLoS One. 2010;5(8):e12197.

    Article  PubMed  CAS  Google Scholar 

  121. Bullinger L, Ehrich M, Dohner K, Schlenk RF, Dohner H, Nelson MR, et al. Quantitative DNA methylation predicts survival in adult acute myeloid leukemia. Blood. 2010;115(3):636–42.

    Article  PubMed  CAS  Google Scholar 

  122. Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010;17(1):13–27.

    Article  PubMed  CAS  Google Scholar 

  123. Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006;24(24):3895–903.

    Article  PubMed  CAS  Google Scholar 

  124. Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K, et al. Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia. Eur J Haematol. 2009;83(2):90–8.

    Article  PubMed  CAS  Google Scholar 

  125. Dombret H. Gene mutation and AML pathogenesis. Blood. 2011;118(20):5366–7.

    Article  PubMed  CAS  Google Scholar 

  126. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A, 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):3740–6.

    Article  PubMed  CAS  Google Scholar 

  127. Gale RE, Hills R, Pizzey AR, Kottaridis PD, Swirsky D, Gilkes AF, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood. 2005;106(12):3768–76.

    Article  PubMed  CAS  Google Scholar 

  128. Care RS, Valk PJ, Goodeve AC, Abu-Duhier FM, Geertsma-Kleinekoort WM, Wilson GA, et al. Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br J Haematol. 2003;121(5):775–7.

    Article  PubMed  CAS  Google Scholar 

  129. Shimada A, Taki T, Tabuchi K, Tawa A, Horibe K, Tsuchida M, et al. KIT mutations, and not FLT3 internal tandem duplication, are strongly associated with a poor prognosis in pediatric acute myeloid leukemia with t(8;21): a study of the Japanese Childhood AML Cooperative Study Group. Blood. 2006;107(5):1806–9.

    Article  PubMed  CAS  Google Scholar 

  130. Oyarzo MP, Lin P, Glassman A, Bueso-Ramos CE, Luthra R, Medeiros LJ. Acute myeloid leukemia with t(6;9)(p23;q34) is associated with dysplasia and a high frequency of flt3 gene mutations. Am J Clin Pathol. 2004;122(3):348–58.

    Article  PubMed  CAS  Google Scholar 

  131. Slovak ML, Gundacker H, Bloomfield CD, Dewald G, Appelbaum FR, Larson RA, et al. A retrospective study of 69 patients with t(6;9)(p23;q34) AML emphasizes the need for a prospective, multicenter initiative for rare ‘poor prognosis’ myeloid malignancies. Leukemia. 2006;20(7):1295–7.

    Article  PubMed  CAS  Google Scholar 

  132. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, 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):4326–35.

    Article  PubMed  CAS  Google Scholar 

  133. Thol F, Kolking B, Damm F, Reinhardt K, Klusmann JH, Reinhardt D, et al. Next-generation sequencing for minimal residual disease monitoring in acute myeloid leukemia patients with FLT3-ITD or NPM1 mutations. Genes Chromosomes Cancer. 2012;51(7):689–95.

    Article  PubMed  CAS  Google Scholar 

  134. Welch JS, Westervelt P, Ding L, Larson DE, Klco JM, Kulkarni S, et al. Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA. 2011;305(15):1577–84.

    Article  PubMed  CAS  Google Scholar 

  135. Cloonan N, Grimmond SM. Transcriptome content and dynamics at single-nucleotide resolution. Genome Biol. 2008;9(9):234.

    Article  PubMed  CAS  Google Scholar 

  136. Chatterjee A, Stockwell PA, Rodger EJ, Morison IM. Comparison of alignment software for genome-wide bisulphite sequence data. Nucleic Acids Res. 2012;40(10):e79.

    Article  PubMed  CAS  Google Scholar 

  137. Ahn JY, Seo K, Weinberg O, Boyd SD, Arber DA. A comparison of two methods for screening CEBPA mutations in patients with acute myeloid leukemia. J Mol Diagn. 2009;11(4):319–23.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Gerald Wertheim and Adam Bagg received support from the J.P. McCarthy Foundation. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Gerald B. W. Wertheim

  2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Gerald B. W. Wertheim & Adam Bagg

  3. Abramson Cancer Center, Philadelphia, PA, USA

    Elizabeth Hexner

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  1. Gerald B. W. Wertheim
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Correspondence to Adam Bagg.

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Wertheim, G.B.W., Hexner, E. & Bagg, A. Molecular-Based Classification of Acute Myeloid Leukemia and Its Role in Directing Rational Therapy. Mol Diagn Ther 16, 357–369 (2012). https://doi.org/10.1007/s40291-012-0009-0

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