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Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype

Oncogene volume 24, pages 1580–1588 (2005)Cite this article

Abstract

In acute myeloid leukemia (AML), constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplications (FLT3-ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (FLT3-TKD), as well as point mutations of the NRAS gene (NRAS-PM) are among the most frequent somatic gene mutations. To elucidate whether these mutations cause aberrant signal transduction in AML, we used gene expression profiling in a series of 110 newly diagnosed AML patients with normal karyotype. The different algorithms used for data analysis revealed highly concordant sets of genes, indicating that the identified gene signatures are specific for each analysed subgroup. Whereas samples with FLT3-ITD and FLT3-TKD could be separated with up to 100% accuracy, this did not apply for NRAS-PM and wild-type samples, suggesting that only FLT3-ITD and FLT3-TKD are associated with an apparent signature in AML. The set of discriminating genes included several known genes, which are involved in cell cycle control (CDC14A, WEE1), gene transcription (HOXB5, FOXA1), and signal transduction (SMG1). In conclusion, we showed that unique gene expression patterns can be correlated with FLT3-ITD and FLT3-TKD. This might lead to the identification of further pathogenetic relevant candidate genes particularly in AML with normal karyotype.

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Acknowledgements

We thank Heidi Kramer for her excellent technical assistance. This study was supported by two grants of the Bundesministerium für Bildung und Forschung (FKZ 01 KW 9937 and NGFN, 01 GR 0101). KN is scholar of the Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS 2001/NAT-3).

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Authors and Affiliations

  1. Division of Molecular Genetics (B060), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Kai Neben, Björn Tews, Felix Kokocinski, Meinhard Hahn & Peter Lichter

  2. Laboratory for Leukemia Diagnostic, Department of Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, D-81366, Munich, Germany

    Susanne Schnittger, Torsten Haferlach, Wolfgang Hiddemann & Claudia Schoch

  3. Division of Intelligent Bioinformatics Systems (B080), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    Benedikt Brors, Jasmin Müller & Roland Eils

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  1. Kai Neben
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Correspondence to Peter Lichter.

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Neben, K., Schnittger, S., Brors, B. et al. Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype. Oncogene 24, 1580–1588 (2005). https://doi.org/10.1038/sj.onc.1208344

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