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Prognostic significance of expression levels of stem cell regulators MSI2 and NUMB in acute myeloid leukemia

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Abstract

Deregulation of the hematopoietic stem cell (HSC) compartment represents a hallmark of acute myeloid leukemia (AML). Recently, in vivo screening for genes that are involved in the regulation of HSCs has led to the discovery of Musashi-2 (MSI2) as a key regulator of HSCs and as a suppressor of NUMB. In order to analyze the prognostic importance of MSI2 and NUMB expression in AML, MSI2 and NUMB transcript levels from 454 AML patients treated in multicenter trials AML SHG 0199 (ClinicalTrials Identifier NCT00209833) and 0295, and 38 healthy volunteers were analyzed by reverse transcriptase PCR in the context of other molecular markers (NPM1, FLT3, CEBPA, IDH1/IDH2, DNMT3A, NRAS, WT1, KIT, MN1, BAALC, ERG, and WT1). In AML, patients with high MSI2 expression were more likely to be FLT3-ITD positive (P < .001), NPM1 (P < .001), and DNMT3A (P = .003) mutated. Overall survival (OS) was shorter in AML patients with high MSI2 expression (hazard ratio, 1.48; 95 % confidence interval, 1.13–1.95, P = .005). However, relapse-free survival (RFS, P = .15) and complete remission (CR, P = .39) rates were not influenced by MSI2 expression. In multivariate analysis, MSI2 expression remained an independent prognostic factor for OS (P = .03). NUMB expression had no impact on survival (OS, P = .47; RFS, P = .59) and CR rate (P = .39). MSI2 but not NUMB is associated with shorter OS in AML patients and may indicate a more aggressive form of AML.

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Acknowledgments

We are indebted to all patients and contributing doctors. We thank Kerstin Görlich, Martin Wichmann, Elvira Lux, and Sylvia Horter for their excellent support. We thank Prof. R. Blasczyk for the supply of healthy control samples. This study was supported by the Deutsche Krebshilfe e.V (grant no. 109003), grant no. DJCLS R 10/22 from the Deutsche-José-Carreras Leukämie-Stiftung e.V, grant no. M 47.1 from the H. W. & J. Hector Stiftung, the Dieter-Schlag-Stiftung grant 2011, German Federal Ministry of Education and research grant number 01EO0802, DFG grant HE 5240/4-1 and TH 1779/1-1, and HiLF grant from Hannover Medical School awarded to FT.

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The authors indicated no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Felicitas Thol, Claudia Winschel, Ann-Kathrin Sonntag, Frederik Damm, Katharina Wagner, Anuhar Chaturvedi, Jürgen Krauter, Arnold Ganser & Michael Heuser

  2. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    Gudrun Göhring & Brigitte Schlegelberger

  3. Department of Hematology-Oncology, University of Freiburg Medical Center, Freiburg, Germany

    Michael Lübbert

  4. Department of Medicine II, Oncological Center, Hubertus Wald University Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Walter Fiedler

  5. Department of Internal Medicine III, Krankenhaus Siloah, Hannover, Germany

    Hartmut Kirchner

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  1. Felicitas Thol
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  2. Claudia Winschel
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  3. Ann-Kathrin Sonntag
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Correspondence to Felicitas Thol.

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Arnold Ganser and Michael Heuser have shared senior authorship.

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Thol, F., Winschel, C., Sonntag, AK. et al. Prognostic significance of expression levels of stem cell regulators MSI2 and NUMB in acute myeloid leukemia. Ann Hematol 92, 315–323 (2013). https://doi.org/10.1007/s00277-012-1637-5

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  • DOI: https://doi.org/10.1007/s00277-012-1637-5

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