Current Oncology Reports

, Volume 14, Issue 5, pp 359–368 | Cite as

Acute Myeloid Leukemia with Normal Cytogenetics

Leukemia (A Aguayo, Section Editor)

Abstract

Acute myeloid leukemia (AML) is proving to be a heterogeneous disease process that is driven by various genetic mutations and aberrant protein expression. As our population ages, the incidence of AML is likely to increase, with approximately a third of adult cases categorized with normal cytogenetics. Advances in technology are now allowing us to explore the genetic expression and protein transcription patterns of AML, providing more information that must find its place in the prognosis and the therapeutic algorithm of this disease. As we learn more, we hope to further categorize patients with normal karyotype AML into discrete risk categories that will help in treatment decision making and further elucidate the necessity for hematopoietic cell transplantation. However, at this time, many of the identified mutations and expression patterns are still experimental, requiring further analysis to determine their exact role in AML.

Keywords

Acute myeloid leukemia AML Normal cytogenetics Normal karyotype Intermediate risk 

References

  1. 1.
    Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, 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;115:453–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Rosnet O, Matteï MG, Marchetto S, Birnbaum D. Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene. Genomics. 1991;9:380–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65:1143–52.PubMedCrossRefGoogle Scholar
  4. 4.
    Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Lisovsky M, Estrov Z, Zhang X, Consoli U, Sanchez-Williams G, Snell V, et al. Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood. 1996;88:3987–97.PubMedGoogle Scholar
  7. 7.
    Fröhling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K, 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;100:4372–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA, 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;98:1752–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B Study. Cancer Res. 2001;61:7233–9.PubMedGoogle Scholar
  10. 10.
    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;111:2776–84.PubMedCrossRefGoogle Scholar
  11. 11.
    Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. 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;110:1262–70.PubMedCrossRefGoogle Scholar
  12. 12.
    Whitman SP, Ruppert AS, Radmacher MD, Mrózek K, Paschka P, Langer C, 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;111:1552–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters–an analysis of 3082 patients. Blood. 2008;111:2527–37.PubMedCrossRefGoogle Scholar
  14. 14.
    Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol. 2010;28:4339–45.PubMedCrossRefGoogle Scholar
  15. 15.
    Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, et al. Sorafenib treatment of FLT3-ITD+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non-responsiveness associated with a D835 mutation. Blood. 2012;119(22):5133–43PubMedCrossRefGoogle Scholar
  16. 16.
    Rau R, Brown P. Nucleophosmin (NPM1) mutations in adult and childhood acute myeloid leukaemia: towards definition of a new leukaemia entity. Hematol Oncol. 2009;27:171–81.PubMedCrossRefGoogle Scholar
  17. 17.
    Falini B, Nicoletti I, Bolli N, Martelli MP, Liso A, Gorello P, et al. Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. Haematologica. 2007;92:519–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Verhaak RG, Goudswaard CS, van Putten W, Bijl MA, Sanders MA, Hugens W, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106:3747–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Döhner K, Schlenk RF, Habdank M, Scholl C, Rücker 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;106:3740–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28:596–604.PubMedCrossRefGoogle Scholar
  21. 21.
    Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–18.PubMedCrossRefGoogle Scholar
  22. 22.
    Schlenk RF, Döhner K, Kneba M, Götze K, Hartmann F, Del Valle F, et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica. 2009;94:54–60.PubMedCrossRefGoogle Scholar
  23. 23.
    Burnett AK, Hills RK, Green C, Jenkinson S, Koo K, Patel Y, et al. The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA. Blood. 2010;115:948–56.PubMedCrossRefGoogle Scholar
  24. 24.
    Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998;18:4301–14.PubMedGoogle Scholar
  25. 25.
    Döhner K, Döhner H. Molecular characterization of acute myeloid leukemia. Haematologica. 2008;93:976–82.PubMedCrossRefGoogle Scholar
  26. 26.
    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;100:2717–23.PubMedCrossRefGoogle Scholar
  27. 27.
    Fröhling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S, 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;22:624–33.PubMedCrossRefGoogle Scholar
  28. 28.
    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;28:570–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. 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;113:3088–91.PubMedCrossRefGoogle Scholar
  30. 30.
    Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. 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;28:2739–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2009;113:6411–8.PubMedCrossRefGoogle Scholar
  32. 32.
    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;363:2424–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Thol F, Damm F, Lüdeking A, Winschel C, Wagner K, Morgan M, et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol. 2011;29:2889–96.PubMedCrossRefGoogle Scholar
  34. 34.
    Hou HA, Kuo YY, Liu CY, Chou WC, Lee MC, Chen CY, et al. DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood. 2012;119:559–68.PubMedCrossRefGoogle Scholar
  35. 35.
    Marková J, Michková P, Burčková K, Březinová J, Michalová K, Dohnalová 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.PubMedCrossRefGoogle Scholar
  36. 36.
    Ribeiro AF, Pratcorona M, Erpelinck-Verschueren C, Rockova V, Sanders M, Abbas S, et al. Mutant DNMT3A: a new marker of poor prognosis in acute myeloid leukemia. Blood. 2012.Google Scholar
  37. 37.
    Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrózek K, 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;30:742–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Metzeler KH, Walker A, Geyer S, Garzon R, Klisovic RB, Bloomfield CD, et al. DNMT3A mutations and response to the hypomethylating agent decitabine in acute myeloid leukemia. Leukemia. 2012;26:1106–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Patel JP, Gönen 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;366:1079–89.PubMedCrossRefGoogle Scholar
  40. 40.
    Döhner K, Tobis K, Ulrich R, Fröhling S, Benner A, Schlenk RF, et al. Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: a study of the Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol. 2002;20:3254–61.PubMedCrossRefGoogle Scholar
  41. 41.
    Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T, et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia. 2000;14:796–804.PubMedCrossRefGoogle Scholar
  42. 42.
    Whitman SP, Liu S, Vukosavljevic T, Rush LJ, Yu L, Liu C, et al. The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. Blood. 2005;106:345–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.PubMedCrossRefGoogle Scholar
  44. 44.
    Marcucci G, Maharry K, Wu YZ, Radmacher MD, Mrózek K, Margeson D, 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;28:2348–55.PubMedCrossRefGoogle Scholar
  45. 45.
    Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Schnittger S, Haferlach C, Ulke M, Alpermann T, Kern W, Haferlach T. 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;116:5486–96.PubMedCrossRefGoogle Scholar
  47. 47.
    Chou WC, Lei WC, Ko BS, Hou HA, Chen CY, Tang JL, et al. The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia. Leukemia. 2011;25:246–53.PubMedCrossRefGoogle Scholar
  48. 48.
    Thol F, Damm F, Wagner K, Göhring G, Schlegelberger B, Hoelzer D, et al. Prognostic impact of IDH2 mutations in cytogenetically normal acute myeloid leukemia. Blood. 2010;116:614–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Gaidzik VI, Schlenk RF, Moschny S, Becker A, Bullinger L, Corbacioglu A, et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood. 2009;113:4505–11.PubMedCrossRefGoogle Scholar
  50. 50.
    Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrózek K, Maharry K, et al. Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol. 2008;26:4595–602.PubMedCrossRefGoogle Scholar
  51. 51.
    Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J, et al. Mutation of the Wilms’ tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: the United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 2008;26:5429–35.PubMedCrossRefGoogle Scholar
  52. 52.
    Hou HA, Huang TC, Lin LI, Liu CY, Chen CY, Chou WC, et al. WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood. 2010;115:5222–31.PubMedCrossRefGoogle Scholar
  53. 53.
    Damm F, Heuser M, Morgan M, Yun H, Grosshennig A, Göhring G, et al. Single nucleotide polymorphism in the mutational hotspot of WT1 predicts a favorable outcome in patients with cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2010;28:578–85.PubMedCrossRefGoogle Scholar
  54. 54.
    Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL, et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood. 2000;96:2862–9.PubMedGoogle Scholar
  55. 55.
    Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Röck J, Paschka P, 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;29:1364–72.PubMedCrossRefGoogle Scholar
  56. 56.
    Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH, 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;114:5352–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S. Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107:3847–53.PubMedCrossRefGoogle Scholar
  58. 58.
    Tanner SM, Austin JL, Leone G, Rush LJ, Plass C, Heinonen K, et al. BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia. Proc Natl Acad Sci U S A. 2001;98:13901–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Langer C, Radmacher MD, Ruppert AS, Whitman SP, Paschka P, Mrózek K, et al. High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood. 2008;111:5371–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Haferlach C, Kern W, Schindela S, Kohlmann A, Alpermann T, Schnittger 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;51:257–65.PubMedCrossRefGoogle Scholar
  61. 61.
    Schwind S, Marcucci G, Maharry K, Radmacher MD, Mrózek 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;116:5660–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Metzeler KH, Dufour A, Benthaus T, Hummel M, Sauerland MC, Heinecke A, et al. ERG expression is an independent prognostic factor and allows refined risk stratification in cytogenetically normal acute myeloid leukemia: a comprehensive analysis of ERG, MN1, and BAALC transcript levels using oligonucleotide microarrays. J Clin Oncol. 2009;27:5031–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G, et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood. 2003;102:1613–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Baldus CD, Thiede C, Soucek S, Bloomfield CD, Thiel E, Ehninger G. BAALC expression and FLT3 internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics: prognostic implications. J Clin Oncol. 2006;24:790–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Eisfeld AK, Marcucci G, Maharry K, Schwind S, Radmacher MD, Nicolet D, et al. miR-3151 interplays with its host gene BAALC and independently impacts on outcome of patients with cytogenetically normal acute myeloid leukemia. Blood. 2012.Google Scholar
  66. 66.
    Marcucci G, Baldus CD, Ruppert AS, Radmacher MD, Mrózek K, Whitman SP, et al. Overexpression of the ETS-related gene, ERG, predicts a worse outcome in acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B Study. J Clin Oncol. 2005;23:9234–42.PubMedCrossRefGoogle Scholar
  67. 67.
    Marcucci G, Maharry K, Whitman SP, Vukosavljevic T, Paschka P, Langer C, et al. High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol. 2007;25:3337–43.PubMedCrossRefGoogle Scholar
  68. 68.
    Schwind S, Marcucci G, Kohlschmidt J, Radmacher MD, Mrózek K, Maharry K, et al. Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia. Blood. 2011;118:4188–98.PubMedCrossRefGoogle Scholar
  69. 69.
    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;27:3198–204.PubMedCrossRefGoogle Scholar
  70. 70.
    Heuser M, Beutel G, Krauter J, Döhner K, von Neuhoff N, Schlegelberger B, et al. High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood. 2006;108:3898–905.PubMedCrossRefGoogle Scholar
  71. 71.
    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;350:1617–28.PubMedCrossRefGoogle Scholar
  72. 72.
    Bullinger L, Döhner K, Bair E, Fröhling S, Schlenk RF, Tibshirani R, et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med. 2004;350:1605–16.PubMedCrossRefGoogle Scholar
  73. 73.
    Radmacher MD, Marcucci G, Ruppert AS, Mrózek K, Whitman SP, Vardiman JW, 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;108:1677–83.PubMedCrossRefGoogle Scholar
  74. 74.
    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.PubMedCrossRefGoogle Scholar
  75. 75.
    Sjøholt G, Bedringaas SL, Døskeland AP, Gjertsen BT. Proteomic strategies for individualizing therapy of acute myeloid leukemia (AML). Curr Pharm Biotechnol. 2006;7:159–70.PubMedCrossRefGoogle Scholar
  76. 76.
    Kornblau SM, Tibes R, Qiu YH, Chen W, Kantarjian HM, Andreeff M, et al. Functional proteomic profiling of AML predicts response and survival. Blood. 2009;113:154–64.PubMedCrossRefGoogle Scholar
  77. 77.
    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;17:13–27.PubMedCrossRefGoogle Scholar
  78. 78.
    Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci U S A. 2008;105:15535–40.PubMedCrossRefGoogle Scholar
  79. 79.
    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;111:3183–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Mrózek K, Marcucci G, Paschka P, Whitman SP, 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;109:431–48.PubMedCrossRefGoogle Scholar
  81. 81.
    Debernardi S, Skoulakis S, Molloy G, Chaplin T, Dixon-McIver A, Young BD. MicroRNA miR-181a correlates with morphological sub-class of acute myeloid leukaemia and the expression of its target genes in global genome-wide analysis. Leukemia. 2007;21:912–6.PubMedGoogle Scholar
  82. 82.
    Marcucci G, Maharry K, Radmacher MD, Mrózek K, Vukosavljevic T, Paschka P, et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study. J Clin Oncol. 2008;26:5078–87.PubMedCrossRefGoogle Scholar
  83. 83.
    Schwind S, Maharry K, Radmacher MD, Mrózek 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;28:5257–64.PubMedCrossRefGoogle Scholar
  84. 84.
    Marcucci G, Radmacher MD, Maharry K, Mrózek K, Ruppert AS, Paschka P, et al. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1919–28.PubMedCrossRefGoogle Scholar
  85. 85.
    Wheatley K, Burnett AK, Goldstone AH, Gray RG, Hann IM, Harrison CJ, et al. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties. Br J Haematol. 1999;107:69–79.PubMedCrossRefGoogle Scholar
  86. 86.
    Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A, et al. Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood. 2003;101:64–70.PubMedCrossRefGoogle Scholar
  87. 87.
    Estey EH, Shen Y, Thall PF. Effect of time to complete remission on subsequent survival and disease-free survival time in AML, RAEB-t, and RAEB. Blood. 2000;95:72–7.PubMedGoogle Scholar
  88. 88.
    Yanada M, Borthakur G, Garcia-Manero G, Ravandi F, Faderl S, Pierce S, et al. Blood counts at time of complete remission provide additional independent prognostic information in acute myeloid leukemia. Leuk Res. 2008;32:1505–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol. 2011;29:1190–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Buccisano F, Maurillo L, Del Principe MI, Del Poeta G, Sconocchia G, Lo-Coco F, et al. Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia. Blood. 2012;119:332–41.PubMedCrossRefGoogle Scholar
  92. 92.
    Marcucci G, Mrózek K, Ruppert AS, Archer KJ, Pettenati MJ, Heerema NA, et al. Abnormal cytogenetics at date of morphologic complete remission predicts short overall and disease-free survival, and higher relapse rate in adult acute myeloid leukemia: results from Cancer and Leukemia Group B Study 8461. J Clin Oncol. 2004;22:2410–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Buccisano F, Maurillo L, Spagnoli A, Del Principe MI, Fraboni D, Panetta P, et al. Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia. Blood. 2010;116:2295–303.PubMedCrossRefGoogle Scholar
  94. 94.
    Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301:2349–61.PubMedCrossRefGoogle Scholar
  95. 95.
    Yanada M, Matsuo K, Emi N, Naoe T. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer. 2005;103:1652–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Cornelissen JJ, van Putten WL, Verdonck LF, Verdonck LF, Theobald M, Jacky E, et al. Results of a HOVON/SAKK donor vs no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109:3658–66.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  2. 2.Department of Medicine, Division of Medical OncologyUniversity of WashingtonSeattleUSA
  3. 3.SeattleUSA

Personalised recommendations