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Acute Leukemias

Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations

Leukemia volume 23, pages 1049–1053 (2009)Cite this article

Abstract

We recently described oncogenic and anti-apoptotic C-RAF germline mutations in patients with therapy-related acute myeloid leukemia (t-AML). Activation of the RAF effector ERK was restricted to transformed cells, suggesting the requirement for cooperating events in leukemogenesis. Western blot analysis of blast cells from patients with C-RAF germline mutations revealed loss of the tumor and metastasis suppressor RAF kinase inhibitor protein (RKIP). Immunohistochemistry of the patients’ primary tumors revealed normal RKIP expression levels, indicating that the loss of RKIP is a somatic, t-AML-specific event. In focus formation assays, the oncogenic potential of human mutant C-RAF was strongly influenced by expression levels of RKIP. Although the number of colonies formed by C-RAFS427G was significantly increased by RKIP silencing, the opposite was observed after RKIP overexpression. These results show that the loss of RKIP is a functional somatic event in carriers of C-RAF germline mutations, which contributes to the development of t-AML.

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Acknowledgements

We thank Walter Kolch, Oliver Rath and Suzanne Hagan for providing RKIP antibodies and expression constructs. We further thank Werner Linkesch for his continuing research support, Sylvia Schauer for her technical assistance and Eugenia Lamont for editing this paper. This work was supported by grants from Land Steiermark (for AZ and HS), Leukämiehilfe Steiermark (for HS), Tiroler Krebshilfe and the Austrian Scientific Fund (for JT). AZ was further supported by an EMBO long-term fellowship and Cancer Research UK.

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  1. A Zebisch and M Haller: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Medical University of Graz, Graz, Austria

    A Zebisch, K Hiden & H Sill

  2. The Beatson Institute for Cancer Research, Glasgow, UK

    A Zebisch

  3. Department of Visceral, Daniel Swarovski Research Laboratory, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria

    M Haller, T Goebel & J Troppmair

  4. Institute of Pathology, Medical University of Graz, Graz, Austria

    G Hoefler

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  1. A Zebisch
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  2. M Haller
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  6. J Troppmair
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  7. H Sill
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Correspondence to H Sill.

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Zebisch, A., Haller, M., Hiden, K. et al. Loss of RAF kinase inhibitor protein is a somatic event in the pathogenesis of therapy-related acute myeloid leukemias with C-RAF germline mutations. Leukemia 23, 1049–1053 (2009). https://doi.org/10.1038/leu.2009.68

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