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Gene expression profiling in AML with normal karyotype can predict mutations for molecular markers and allows novel insights into perturbed biological pathways

Leukemia volume 24, pages 1216–1220 (2010)Cite this article

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Acute myeloid leukemia (AML) is a heterogeneous disease, and AML with normal karyotype (AML-NK) is categorized as an intermediate-risk group based on cytogenetic stratification. However, molecular analyses successfully identified biomarkers that further allowed dissecting clinically meaningful subgroups. In AML-NK, acquired mutations with prognostic relevance were identified for FLT3, CEBPA, and NPM1.1 FLT3-internal tandem duplication (ITD) mutations were associated with short relapse-free and overall survival, whereas mutations in CEBPA or NPM1—without concomitant FLT3-ITD—had a more favorable outcome.2

Here, we present gene expression profiles of 251 de novo AML-NK cases. In three centers, microarray analyses were performed to delineate robust expression signatures for molecular markers and to elucidate the disturbance of cellular growth, proliferation, and differentiation processes in this disease.

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References

  1. Haferlach T . Molecular genetic pathways as therapeutic targets in acute myeloid leukemia. Hematol Am Soc Hematol Educ Program 2008; 2008: 400–411.

    Article  Google Scholar 

  2. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909–1918.

    Article  CAS  PubMed  Google Scholar 

  3. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66.

    Article  CAS  PubMed  Google Scholar 

  4. 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: 3733–3739.

    Article  CAS  PubMed  Google Scholar 

  5. 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: 4326–4335.

    Article  CAS  PubMed  Google Scholar 

  6. 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: 4011–4020.

    Article  CAS  PubMed  Google Scholar 

  7. Kohlmann A, Kipps TJ, Rassenti LZ, Downing JR, Shurtleff SA, Mills KI et al. An international standardization programme towards the application of gene expression profiling in routine leukaemia diagnostics: the Microarray Innovations in LEukemia study prephase. Br J Haematol 2008; 142: 802–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kohlmann A, Haschke-Becher E, Wimmer B, Huber-Wechselberger A, Meyer-Monard S, Huxol H et al. Intraplatform reproducibility and technical precision of gene expression profiling in 4 laboratories investigating 160 leukemia samples: the DACH study. Clin Chem 2008; 54: 1705–1715.

    Article  CAS  PubMed  Google Scholar 

  9. 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: 254–266.

    Article  CAS  PubMed  Google Scholar 

  10. Alcalay M, Tiacci E, Bergomas R, Bigerna B, Venturini E, Minardi SP et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc+ AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood 2005; 106: 899–902.

    Article  CAS  PubMed  Google Scholar 

  11. Verhaak RG, Goudswaard CS, van PW, 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: 3747–3754.

    Article  CAS  PubMed  Google Scholar 

  12. The Gene Ontology project in 2008. Nucleic Acids Res 2008; 36: D440–D444.

  13. Efron B, Tibshirani R . On testing the significance of sets of genes. Ann Appl Stat 2007; 1: 107–129.

    Article  Google Scholar 

  14. Wouters BJ, Jorda MA, Keeshan K, Louwers I, Erpelinck-Verschueren CA, Tielemans D et al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood 2007; 110: 3706–3714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wouters BJ, Lowenberg 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: 3088–3091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bullinger L, Dohner K, Kranz R, Stirner C, Frohling S, Scholl C et al. An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML. Blood 2008; 111: 4490–4495.

    Article  CAS  PubMed  Google Scholar 

  17. Verhaak RG, Wouters BJ, Erpelinck CA, Abbas S, Beverloo HB, Lugthart S et al. Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica 2009; 94: 131–134.

    Article  PubMed  Google Scholar 

  18. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edn IARC: Lyon, France, 2008.

    Google Scholar 

  19. Ioannidis JP, Allison DB, Ball CA, Coulibaly I, Cui X, Culhane AC et al. Repeatability of published microarray gene expression analyses. Nat Genet 2009; 41: 149–155.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. MLL Munich Leukemia Laboratory, Munich, Germany

    A Kohlmann, S Schnittger & T Haferlach

  2. Internal Medicine III, University of Ulm, Ulm, Germany

    L Bullinger, K Döhner & H Döhner

  3. Medical Clinic I, University Hospital, Dresden, Germany

    C Thiede, M Schaich & G Ehninger

  4. Department of Medical Informatics and Biomathematics, University of Münster, M, ü, nster, Germany

    M Dugas & H-U Klein

Authors
  1. A Kohlmann
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  2. L Bullinger
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  3. C Thiede
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  4. M Schaich
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  5. S Schnittger
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  6. K Döhner
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  7. M Dugas
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  8. H-U Klein
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  11. T Haferlach
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Corresponding author

Correspondence to A Kohlmann.

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Competing interests

Microarray study supplies as well as sample preparation and microarray technology training courses were provided by Roche Molecular Systems Inc. (Pleasanton, CA, USA) as part of the AmpliChip Leukemia research program, a collaborative effort with the European LeukemiaNet addressing gene expression signatures in leukemia. Research in this work was further supported in part by COST Action BM0801: European Genomic and Epigenetic Study on MDS and AML and the gene-profiling group (Work package 13) of the European LeukemiaNet. TH is employed by MLL Munich Leukemia Laboratory GmbH, has equity ownership of MLL Munich Leukemia Laboratory GmbH, and has been a consultant during study conduct for F. Hoffmann-La Roche Ltd., Basel, Switzerland. AK was employed by Roche Molecular Systems Inc., during study conduct and is now employed by MLL Munich Leukemia Laboratory GmbH. SS has equity ownership of MLL Munich Leukemia Laboratory GmbH. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

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Kohlmann, A., Bullinger, L., Thiede, C. et al. Gene expression profiling in AML with normal karyotype can predict mutations for molecular markers and allows novel insights into perturbed biological pathways. Leukemia 24, 1216–1220 (2010). https://doi.org/10.1038/leu.2010.73

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