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Cytogenetics and Molecular Genetics

Altered miRNA and gene expression in acute myeloid leukemia with complex karyotype identify networks of prognostic relevance

Leukemia volume 27, pages 353–361 (2013)Cite this article

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Abstract

Recently, the p53-miR-34a network has been identified to have an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-miR-34a axis in a large cohort of CK-AML with known TP53 status (TP53altered, n=57; TP53unaltered, n=31; altered indicates loss and/or mutation of TP53). Profiling microRNA (miRNA) expression delineated TP53 alteration-associated miRNA profiles, and identified miR-34a and miR-100 as the most significantly down- and upregulated miRNA, respectively. Moreover, we found a distinct miR-34a expression-linked gene expression profile enriched for genes belonging to p53-associated pathways, and implicated in cell cycle progression or apoptosis. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53unaltered CK-AML, high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53biallelic altered CK-AML, high miR-34a expression pointed to better OS. Thus, detailed molecular profiling links impaired p53 to decreased miR-34a expression, but also identifies p53-independent miR-34a induction mechanisms as shown in TP53biallelic altered cell lines treated with 15-deoxy-Δ12,14-prostaglandin. An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in TP53altered CK-AML.

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Acknowledgements

Analyses were performed using BRB-ArrayTools developed by Dr Richard Simon and BRB-ArrayTools Development Team. We thank all members of the German-Austrian AML Study Group (AMLSG) for their participation in this study and for providing patient samples. This study was supported in part by the Bundesministerium für Bildung und Forschung (NGFNplus Grant No. 01GS0871), by the Deutsche José Carreras Stiftung e.V. (DJCLS R 06/41v), and LB was supported in part by the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1).

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  1. F G Rücker and A C Russ: These authors contributed equally to the work.

Authors and Affiliations

  1. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    F G Rücker, A C Russ, S Cocciardi, H Kett, R F Schlenk, U Botzenhardt, C Langer, S Fröhling, T Zenz, H Döhner, K Döhner & L Bullinger

  2. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    J Krauter & A Ganser

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

    B Schlegelberger

  4. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    P Lichter

  5. Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany

    T Zenz

  6. Department of Medicine V, University of Heidelberg, Heidelberg, Germany

    T Zenz

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  1. F G Rücker
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Correspondence to L Bullinger.

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Rücker, F., Russ, A., Cocciardi, S. et al. Altered miRNA and gene expression in acute myeloid leukemia with complex karyotype identify networks of prognostic relevance. Leukemia 27, 353–361 (2013). https://doi.org/10.1038/leu.2012.208

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