Seminars in Oncology
Volume 35, Issue 4 , Pages 346-355 , August 2008

Prognostic Implications of Gene Mutations in Acute Myeloid Leukemia With Normal Cytogenetics

  • Verena Gaidzik
    • ,
  • Konstanze Döhner

      Affiliations

    • Corresponding Author InformationAddress correspondence to Konstanze Döhner, MD, Department of Internal Medicine III, University Hospital of Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany.

References 

  1. Fröhling S, Scholl C, Gilliland DG, et al. Genetics of myeloid malignancies—pathogenetic and clinical implications. J Clin Oncol. 2005;23:6285–6295
  2. Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18:115–136
  3. Schlenk RF, Benner A, Krauter J, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;15:3741–3750
  4. Marcucci G, Mrózek K, Ruppero AS, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B Study. J Clin Oncol. 2005;23:5705–5717
  5. Tallman MS, Andersen JW, Schiffer CA, et al. All-transretinoic acid in acute promyelocytic leukemia. N Engl J Med. 337:1021-28
  6. Cheson BD, Bennett JM, Kopecky KJ, 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;21:4642–4649
  7. Estey E, Döhner H. Acute myeloid leukaemia. Lancet. 2006;368:1894–1907
  8. Mrozek K, Heinonen K, Bloomfield CD. Clinical importance of cytogenetics in acute myeloid leukaemia. Best Pract Res Clin Hematol. 2001;14:19–47
  9. Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet. 2002;3:179–198
  10. Castilla LH, Garret L, Adya N, et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet. 1999;23:144–146
  11. Yergeau DA, Hetherington CJ, Wang Q, et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet. 1997;15:303–306
  12. Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet. 1999;23:166–175
  13. Smith ML, Cavenhagh JD, Lister TA, et al. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351:2403–2407
  14. Kelly LM, Kutok JL, Williams IR, et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci U S A. 2002;99:8283–8288
  15. Schessl C, Rawat VP, Cusan M, et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest. 2005;115:2159–2168
  16. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1532–1542
  17. Grisendi S, Mecucci C, Falini B, et al. Nucleophosmin and cancer. Nat Rev. 2006;6:493–505
  18. Falini B, Mecucci C, Tiacci E, et al. Gimema Acute Leukemia Working Party (Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype). N Engl J Med. 2005;352:254–266
  19. Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biological and clinical features. Blood. 2007;109:874–885
  20. Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics—interaction with other gene mutations. Blood. 2005;106:3740–3746
  21. Verhaak RGW, Goudswaard CS, van Putten W, et al. Mutations in nucleophosmin NPM1 in acute myeloid leukemia (AML): association with other genetic abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106:3747–3754
  22. Schnittger S, Schoch C, Kern W, et al. Nucleophosmin gene mutations are predictors of favourable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005;106:3733–3739
  23. Suzuki T, Kiyoi H, Ozeki K, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 2005;106:2854–2861
  24. Boissel N, Renneville A, Biggio V, et al. Relavence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005;106:3618–3620
  25. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006;107:4011–4020
  26. Gallagher RE. Dueling mutations in normal karyotype AML. Blood. 2005;106:3681–3682
  27. Liu H, Tan BC, Tseng KH, et al. Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. EMBO Rep. 2007;8:394–400
  28. Schlenk RF, Fröhling S, Hartmann F, et al. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004;18:1798–1803
  29. Schlenk RF, Döhner K, Kneba M, et al. The genotype NPM1mut/FLT3-ITDneg is a highly significant predictive factor for response to therapy with all-trans-retinoic acid in acute myeloid leukaemia—results from AMLSG trial AML HD98B. [abstract] Blood. 2007;110:297
  30. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918
  31. Yamamoto Y, Kiyoi H, Nakano Y, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–2439
  32. 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;98:1752–1759
  33. Whitman SP, Archer KJ, Feng L, 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;61:7233–7239
  34. Fröhling 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;100:4372–4380
  35. Beran M, Luthra R, Kantarjian H, Estey E. FLT3 mutation and response to intensive chemotherapy in young adult and elderly patients with normal karyotype. Leuk Res. 204;28:547-50
  36. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335
  37. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–665
  38. 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;110:1262–1270
  39. 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 duplication. Blood. 2008;111:1552–1559
  40. Grundler R, Miething C, Thiede C, et al. FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood. 2005;105:4792–4799
  41. Mrózek K, Döhner H, Bloomfield CD. Influence of new molecular prognostic markers in patients with karyotypically normal acute myeloid leukemia: recent advances. Curr Opin Hematol. 2007;14:106–114
  42. Fitzgibbon J, Smith LL, Raghavan M, et al. Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias. Cancer Res. 2005;65:9152–9154
  43. 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;111:2776–2784
  44. Stirewalt DL, Kopecky KJ, Meshinchi S, et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood. 2006;107:3724–3726
  45. Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19:1345–1349
  46. Gale RE, Hills R, Kottaridis PD, et al. NO evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia from the UK MRC AML 10 and 12 trials. Blood. 2005;106:3658–3665
  47. Schlenk RF, Döhner K, Krauter J, et al. Mutations and outcome of treatment in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–1918
  48. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54–60
  49. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669–3676
  50. Fiedler W, Serve H, Döhner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood. 2005;105:986–993
  51. Pabst T, Mueller BU, Zhang P, et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001;3:263–270
  52. Fröhling 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;22:624–633
  53. 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;100:2717–2723
  54. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, Meijer J, et al. Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematol J. 2003;4:31–40
  55. Sellick GS, Spendlove HE, Catovsky D, et al. Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia. Leukemia. 2005;19:1276–1278
  56. Fröhling S, Schlenk RF, Krauter J, et al. Acute myeloid leukemia with deletion 9q within a non-complex karyotype is associated with CEBPA loss-of-function mutations. Genes Chromosomes Cancer. 2005;42:427–432
  57. Strout MP, Marcucci G, Bloomfield CD, Caligiuri MA. The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia. Proc Natl Acad Sci U S A. 1998;95:2390–2395
  58. Whitman SP, Liu S, Vukosavljevic T, 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;106:345–352
  59. Döhner K, Tobis K, Ulrich R, 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 AML Study Group ULM (AMLSG Ulm). J Clin Oncol. 2002;20:3254–3261
  60. Caligiuri MA, Strout MP, Lawrence D, et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res. 1998;58:55–59
  61. Whitman SP, Ruppert AS, Marcucci G, et al. Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study. Blood. 2007;109:5164–5167
  62. Stirewalt DL, Kopecky KJ, Meshinchi S, et al. FLT3, RAS and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001;97:3589–3595
  63. Bacher U, Haferlach T, Schoch C, et al. Implication of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107:3847–3853
  64. 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;106:2113–2119
  65. Ellisen LW, Carlesso N, Cheng T, et al. The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. EMBO J. 2004;20:1897–1909
  66. King-Underwood L, Renshaw J, Pritchard-Jones K. Mutations in the Wilms' tumor gene WT1 in leukemias. Blood. 1996;87:2171–2179
  67. Summers K, Stevens J, Kakkas I, et al. Wilms' tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia. 2007;21:550–551
  68. Gaiger A, Schmid D, Heinze G, et al. Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia. 1998;12:1886–1894
  69. Mueller BU, Pabst T, Osato M, et al. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood. 2002;100:998–1007
  70. Döhner K, Tobis K, Bischof T, et al. Mutation analysis of the transcription factor PU.1 in younger adults (16 to 60 years) with acute myeloid leukemia: a study of the AML Study Group Ulm (AMLSG ULM). Blood. 2003;102:3850
  71. Vegesna V, Takeuchi S, Hofmann WK, et al. C/EBP-beta, C/EBP-delta, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies. Leuk Res. 2002;26:451–457
  72. Lamandin C, Sagot C, Roumier C, et al. Are PU. 1 mutations frequent genetic events in acute myeloid leukemia (AML)? Blood. 2002;100:4680–4681
  73. Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148–150
  74. Xu R, Yu Y, Zheng S, et al. Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia. Blood. 2005;106:3142–3149
  75. Caliguri MA, Briesewitz R, Yu J, Wang L, et al. Novel c-CBL and CBL-b ubiquitin ligase mutations in human acute myeloid leukemia. Blood. 2007;110:1022–1024
  76. Sargin B, Choudhary C, Crosetto N, Schmidt MHH, et al. Flt3-dependent transformation by inactivating c-CBL mutations in AML. Blood. 2007;110:1004–1012

 Supported in part by Grants No. 01GI9981 (Network of Competence Acute and Chronic Leukemias), 01KG0605 [IPD-Meta-Analysis: A model-based hierarchical prognostic system for adult patients with acute myeloid leukemia (AML)] from the Bundesministerium für Bildung und Forschung (BMBF), Germany, the Deutsche José Carreras Leukämie Stiftung (DJCLS R 06/06v), and the Else-Kröner-Fresenius-Stiftung (P38/05//A49/05//F03).

PII: S0093-7754(08)00115-2

doi: 10.1053/j.seminoncol.2008.04.005

Seminars in Oncology
Volume 35, Issue 4 , Pages 346-355 , August 2008

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