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Acute Non-Lymphocytic Leukemias

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia

Leukemia volume 20, pages 437–443 (2006)Cite this article

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with −7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with −7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARα signaling in AML. Ski was co-immunoprecipitated and colocalized with RARα. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARα signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARα signaling.

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Acknowledgements

We thank Dagmar Schwell, Eva Bug, Susanne Rinné and Angelika Filmer for expert technical assistance, as well as all patients and physicians contributing patient samples to this study. This work was supported by grants from the Deutsche José-Carreras Leukämie-Stiftung (DJCLS LR02/05), the ‘Kompetenznetz Akute und chronische Leukämien’ (BMBF 01GI9974) , the ‘Nationales Genomforschungsnetz2’ (BMBF 01GS0449) from the Bundesministerium für Bildung und Forschung and the Deutsche Forschungsgemeinschaft (Transregio TR 17).

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Authors and Affiliations

  1. Klinik für Innere Medizin mit SP Hämatologie, Onkologie und Immunologie, Philipps-Universität, Marburg, Germany

    M Ritter, D Kattmann, S Teichler, M K R Samuelsson, A Burchert, J-P Bach, T D Kim & A Neubauer

  2. Institut für Medizinische Biometrie und Epidemiologie, Philipps-Universität, Marburg, Germany

    O Hartmann, R Jäger & H Schäfer

  3. Institut für Molekularbiologie und Tumorforschung, Philipps-Universität, Marburg, Germany

    B Berwanger & M Eilers

  4. Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany

    C Thiede & G Ehninger

  5. Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY, USA

    N Ueki & M J Hayman

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  1. M Ritter
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Correspondence to A Neubauer.

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Supplementary Information accompanies the paper on Leukemia website (http://www.nature.com/leu).

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Ritter, M., Kattmann, D., Teichler, S. et al. Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia. Leukemia 20, 437–443 (2006). https://doi.org/10.1038/sj.leu.2404093

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