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Genetic abnormalities in acute myelogenous leukemia with normal cytogenetics

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Abstract

Acute myelogenous leukemia (AML) results from a differentiation block of hematopoietic progenitor cells along with uncontrolled proliferation. The cytogenetic abnormality at initial diagnosis is the single most important prognostic factor classifying AML patients into three prognostic categories: favorable, intermediate, and poor risk. Currently, favorable-risk AML patients are usually treated with contemporary chemotherapy, and poor-risk AML patients receive allogeneic stem cell transplantation if suitable stem cell donors exist. The approximately 40% of AML patients without identifiable cytogenetic abnormalities (NC AML) are classified as intermediate risk. The optimal therapeutic strategies for these patients are largely unclear. Emerging data recently suggested that molecular study of the mutations of NPM1, FLT3, MLL, and CEBPα and alterations in expression levels of BAALC, MN1, and ERG may identify poor-risk patients with NC AML. Further prospective studies are needed to confirm whether NC AML patients with poor risk have improved clinical outcomes after more aggressive therapy.

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References and Recommended Reading

  1. Kell J: Emerging treatments in acute myeloid leukaemia. Expert Opin Emerg Drugs 2004, 9:55–71.

    Article  PubMed  CAS  Google Scholar 

  2. Estey EH: General approach to, and perspectives on clinical research in, older patients with newly diagnosed acute myeloid leukemia. Semin Hematol 2006, 43:89–95.

    Article  PubMed  Google Scholar 

  3. Tallmann MS: Curative therapeutic approaches to APL. Ann Hematol 2004, 83(Suppl 1):S81–S82.

    PubMed  Google Scholar 

  4. Mrozek K, Heinonen K, de la Chapelle A, et al.: Clinical significance of cytogenetics in acute myeloid leukemia. Semin Oncol 1997, 24:17–31.

    PubMed  CAS  Google Scholar 

  5. Slovak ML, Kopecky KJ, Cassileth PA, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000, 96:4075–4083.

    PubMed  CAS  Google Scholar 

  6. Chen W, Rassidakis GZ, Medeiros LJ: Nucleophosmin gene mutations in acute myeloid leukemia. Arch Pathol Lab Med 2006, 130:1687–1692.

    PubMed  CAS  Google Scholar 

  7. Verhaak RG, Goudswaard CS, van Putten 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, 106:3747–3754.

    Article  PubMed  CAS  Google Scholar 

  8. Falini B, Mecucci C, Tiacci E, et al.: Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med 2005, 352:254–266.

    Article  PubMed  CAS  Google Scholar 

  9. Grisendi S, Mecucci C, Falini B, et al.: Nucleophosmin and cancer. Nat Rev Cancer 2006, 6:493–505.

    Article  PubMed  CAS  Google Scholar 

  10. Falini B, Nicoletti I, Martelli MF, Mecucci C: Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood 2007, 109:874–885.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. Schnittger S, Schoch C, Kern W, et al.: Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005, 106:3733–3739.

    Article  PubMed  CAS  Google Scholar 

  13. Dohner K, Schlenk RF, Habdank M, et al.: Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005, 106:3740–3746.

    Article  PubMed  CAS  Google Scholar 

  14. Gorello P, Cazzaniga G, Alberti F, et al.: Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006, 20:1103–1108.

    Article  PubMed  CAS  Google Scholar 

  15. Noguera NI, Ammatuna E, Zangrilli D, et al.: Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia. Leukemia 2005, 19:1479–1482.

    Article  PubMed  CAS  Google Scholar 

  16. Larramendy ML, Niini T, Elonen E, et al.: Overexpression of translocation-associated fusion genes of FGFRI, MYC, NPMI, and DEK, but absence of the translocations in acute myeloid leukemia. A microarray analysis. Haematologica 2002, 87:569–577.

    PubMed  CAS  Google Scholar 

  17. Kiyoi H, Naoe T: biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation. Int J Hematol 2006, 83:301–308.

    Article  PubMed  CAS  Google Scholar 

  18. Zheng R, Small D: Mutant FLT3 signaling contributes to a block in myeloid differentiation. Leuk Lymphoma 2005, 46:1679–1687.

    Article  PubMed  CAS  Google Scholar 

  19. 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, 100:4372–4380.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. Kiyoi H, Yanada M, Ozekia K: Clinical significance of FLT3 in leukemia. Int J Hematol 2005, 82:85–92.

    Article  PubMed  CAS  Google Scholar 

  22. Liang DC, Shih LY, Hung IJ, et al.: FLT3-TKD mutation in childhood acute myeloid leukemia. Leukemia 2003, 17:883–886.

    Article  PubMed  CAS  Google Scholar 

  23. Bienz M, Ludwig M, Leibundgut EO, et al.: Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res 2005, 11:1416–1424.

    Article  PubMed  CAS  Google Scholar 

  24. Kainz B, Heintel D, Marculescu R, et al.: Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16). Hematol J 2002, 3:283–289.

    Article  PubMed  CAS  Google Scholar 

  25. Ciolli S, Vannucchi AM, Leoni F, et al.: Internal tandem duplications of Flt3 gene (Flt3/ITD) predicts a poor post-remission outcome in adult patients with acute non-promyelocytic leukemia. Leuk Lymphoma 2004, 45:73–78.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    PubMed  CAS  Google Scholar 

  28. 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.

    Article  PubMed  CAS  Google Scholar 

  29. Ozeki K, Kiyoi H, Hirose Y, et al.: Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 2004, 103:1901–1908.

    Article  PubMed  CAS  Google Scholar 

  30. 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 AML10 and 12 trials. Blood 2005, 106:3658–3665.

    Article  PubMed  CAS  Google Scholar 

  31. Sternberg DW, Licht JD: Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges. Curr Opin Hematol 2005, 12:7–13.

    Article  PubMed  CAS  Google Scholar 

  32. Scholl S, Loncarevic IF, Krause C, et al.: Minimal residual disease based on patient specific Flt3-ITD and-ITT mutations in acute myeloid leukemia. Leuk Res 2005, 29:849–853.

    Article  PubMed  CAS  Google Scholar 

  33. Tanner SM, Austin JL, Leone G, 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, 98:13901–13906.

    Article  PubMed  CAS  Google Scholar 

  34. Baldus CD, Tanner SM, Kusewitt DF, et al.: BAALC, a novel marker of human hematopoietic progenitor cells. Exp Hematol 2003, 31:1051–1056.

    PubMed  CAS  Google Scholar 

  35. Baldus CD, Thiede C, Soucek S, et al.: BAALC expression and FLT3 internal tandem duplication mutations in acute myeloid leukemia patients with normal cytogenetics: prognostic implications. J Clin Oncol 2006, 24:790–797.

    Article  PubMed  CAS  Google Scholar 

  36. Baldus CD, Tanner SM, Ruppert AS, 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, 102:1613–1618.

    Article  PubMed  CAS  Google Scholar 

  37. Heuser M, Argiropoulos B, Kuchenbauer F, et al.: MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML. Blood 2007, 110:1639–1647.

    Article  PubMed  CAS  Google Scholar 

  38. van Wely KH, Molijn AC, Buijs A, et al.: The MN1 oncoprotein synergizes with coactivators RAC3 and p300 in RAR-RXR-mediated transcription. Oncogene 2003, 22:699–709.

    Article  PubMed  CAS  Google Scholar 

  39. Carella C, Bonten J, Sirma S, et al.: MN1 overexpression is an important step in the development of inv(16) AML. Leukemia 2007, 21:1679–1690.

    Article  PubMed  CAS  Google Scholar 

  40. Heuser M, Beutel G, Krauter J, et al.: High meningioma 1 (MN1) expression as a predictor for poor outcome in acute myeloid leukemia with normal cytogenetics. Blood 2006, 108:3898–3905.

    Article  PubMed  CAS  Google Scholar 

  41. Yu BD, Hess JL, Horning SE, et al.: Altered Hox expression and segmental identity in Mll-mutant mice. Nature 1995, 378:505–508.

    Article  PubMed  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. Dohner 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 Acute Myeloid Leukemia Study Group Ulm. J Clin Oncol 2002, 20:3254–3261.

    Article  PubMed  CAS  Google Scholar 

  44. Schnittger S, Kinkelin U, Schoch C, 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.

    Article  PubMed  CAS  Google Scholar 

  45. Weisser M, Kern W, Schoch C, et al.: Risk assessment by monitoring expression levels of partial tandem duplications in the MLL gene in acute myeloid leukemia during therapy. Haematologica 2005, 90:881–889.

    PubMed  CAS  Google Scholar 

  46. Pabst T, Mueller BU, Zhang P, et al.: Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 2001, 27:263–270.

    Article  PubMed  CAS  Google Scholar 

  47. 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.

    Article  PubMed  CAS  Google Scholar 

  48. 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, 22:624–633.

    Article  PubMed  CAS  Google Scholar 

  49. 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.

    Article  PubMed  CAS  Google Scholar 

  50. Baldus CD, Liyanarachchi S, Mrozek K, et al.: Acute myeloid leukemia with complex karyotypes and abnormal chromosome 21: amplification discloses overexpression of APP, ETS2, and ERG genes. Proc Natl Acad Sci U S A, 2004, 101:3915–3920.

    Article  PubMed  CAS  Google Scholar 

  51. Mrozek K, Heinonen K, Theil KS, et al.: Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q. Genes Chromosomes Cancer 2002, 34:137–153.

    Article  PubMed  Google Scholar 

  52. Ichikawa H, Shimizu K, Hayashi Y, et al.: An RNA-binding protein gene, TLS/FUS, is fused to ERG in human myeloid leukemia with t(16;21) chromosomal translocation. Cancer Res 1994, 54:2865–2868.

    PubMed  CAS  Google Scholar 

  53. Marcucci G, Baldus CD, Ruppert AS, 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, 23:9234–9242.

    Article  PubMed  CAS  Google Scholar 

  54. Rainis L, Toki T, Pimanda JE, et al.: The proto-oncogene ERG in megakaryoblastic leukemias. Cancer Res 2005, 65:7596–7602.

    PubMed  CAS  Google Scholar 

  55. Debernardi S, Lillington DM, Chaplin T, et al.: Genome-wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation-mediated fusion events. Genes Chromosomes Cancer 2003, 37:149–158.

    Article  PubMed  CAS  Google Scholar 

  56. Vey N, Mozziconacci MJ, Groulet-Martinec A, et al.: Identification of new classes among acute myelogenous leukaemias with normal karyotype using gene expression profiling. Oncogene 2004, 23:9381–9391.

    Article  PubMed  CAS  Google Scholar 

  57. Valk PJ, Verhaak RG, Beijen MA, et al.: Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004, 350:1617–1628.

    Article  PubMed  CAS  Google Scholar 

  58. Bullinger L, Dohner K, Bair E, et al.: Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 2004, 350:1605–1616.

    Article  PubMed  CAS  Google Scholar 

  59. Radmacher MD, Marcucci G, Ruppert AS, et al.: Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study. Blood 2006, 108:1677–1683.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, Case Comprehensive Cancer Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH, 44106, USA

    William Tse

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  1. David Wald
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  2. Johanna M. Vermaat
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  3. Gil Peleg
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  4. William Tse
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Correspondence to William Tse.

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Wald, D., Vermaat, J.M., Peleg, G. et al. Genetic abnormalities in acute myelogenous leukemia with normal cytogenetics. Curr Hematol Malig Rep 3, 83–88 (2008). https://doi.org/10.1007/s11899-008-0013-y

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