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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia

Leukemia volume 26, pages 1842–1849 (2012)Cite this article

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Abstract

RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen-activated protein kinase/extracellular signal-regulated kinase signaling cascade. We investigated its role in acute myeloid leukemia (AML), an aggressive malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Western blot analysis revealed loss of RKIP expression in 19/103 (18%) primary AML samples and 4/17 (24%) AML cell lines but not in 10 CD34+ HSPC specimens. In in-vitro experiments with myeloid cell lines, RKIP overexpression inhibited cellular proliferation and colony formation in soft agar. Analysis of two cohorts with 103 and 285 AML patients, respectively, established a correlation of decreased RKIP expression with monocytic phenotypes. RKIP loss was associated with RAS mutations and in transformation assays, RKIP decreased the oncogenic potential of mutant RAS. Loss of RKIP further related to a significantly longer relapse-free survival and overall survival in uni- and multivariate analyses. Our data show that RKIP is frequently lost in AML and correlates with monocytic phenotypes and mutations in RAS. RKIP inhibits proliferation and transformation of myeloid cells and decreases transformation induced by mutant RAS. Finally, loss of RKIP seems to be a favorable prognostic parameter in patients with AML.

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Acknowledgements

This work was dedicated in loving memory to Astrid Hwaletz. We thank Werner Linkesch for continuing research support. This study was supported by grants from Land Steiermark (for AZ and HS), Leukämiehilfe Steiermark (for HS), FWF-MCBO (for JT), ÖKH-KG/Tirol (for JT), Cancer Research UK (for AZ and WK) and Science Foundation Ireland under Grant No. 06/CE/B1129 (for AZ and WK). AZ was further supported by an EMBO long-term fellowship.

Author contributions

AZ designed the research and performed the experiments, collected, analyzed and interpreted the data and wrote the manuscript; KL, OW, MH, CB, IF, AD, DP, DM, OR and KB performed the experiments and collected the data; FQ performed statistical analysis; ET and RD provided key research tools, collected, analyzed and interpreted the data; and AW, WK, JT and HS designed the study, collected, analyzed and interpreted the data and wrote the manuscript.

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Author notes

  1. W Kolch, J Troppmair and H Sill: These authors contributed equally to this work.

Authors and Affiliations

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

    A Zebisch, A Wölfler, I Fried, O Wolf, K Lind, C Bodner & H Sill

  2. Systems Biology Ireland, University College Dublin, Dublin, Ireland

    A Zebisch, D Matallanas & W Kolch

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

    A Zebisch, O Rath & K Blyth

  4. Daniel Swarovski Research Laboratory, Innsbruck Medical University, Innsbruck, Austria

    M Haller, A Drasche, D Pirkebner & J Troppmair

  5. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    R Delwel & E Taskesen

  6. Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria

    F Quehenberger

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  1. A Zebisch
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Zebisch, A., Wölfler, A., Fried, I. et al. Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia. Leukemia 26, 1842–1849 (2012). https://doi.org/10.1038/leu.2012.61

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