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Increased leukocyte survival and accelerated onset of lymphoma in the absence of MCL-1 S159-phosphorylation

Oncogene volume 33, pages 5221–5224 (2014)Cite this article

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Abstract

The antiapoptotic BCL-2 protein MCL-1, which opposes mitochondrial outer membrane permeabilization, was shown to have a crucial role in the survival of hematopoietic cells. We have previously shown that, upon loss of phosphatidylinositol 3-kinase signaling, S159 of MCL-1 is phosphorylated by glycogen synthase kinase-3 (GSK-3), earmarking MCL-1 for enhanced ubiquitylation and degradation. In this study, we introduced MCL-1wt or the phosphorylation-deficient mutant MCL-1S159A in mouse BM cells, followed by adoptive transfer to recipient mice. Mice expressing MCL-1S159A exhibited significantly elevated white blood cell and lymphocyte counts, whereas no effect was observed on the distribution of T and B lymphocyte subsets or the numbers of monocytes, red blood cells or platelets. Expression of MCL-1S159A in Eμ-Myc transgenic bone marrow significantly accelerated the onset of disease, and these mice displayed increased spleen weights compared with Eμ-Myc/MCL-1wt mice. Our data demonstrate that the absence of MCL-1 S159 phosphorylation provides a survival advantage for hematopoietic cells in vivo and facilitates oncogenesis.

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Acknowledgements

We thank Martin Brandenburg, Katharina Thumm, Heiko Bauer, Klaus Geiger, Jan Bodinek-Wersing and Karin Neubert. This study was supported by Grants Ma 1967/1 and Ma 1967/2 from the Deutsche Forschungsgemeinschaft to UM, Grants 109199 and 107397 from the Deutsche Krebshilfe to UM the Spemann Graduate School of Biology and Medicine (SGBM, GSC-4) funded by the Excellence Initiative of the German Federal and State Governments, Germany to PBS, FP and UM, by the Centre for Biological Signalling Studies (BIOSS, EXC-294) funded by the Excellence Initiative, Germany to UM and CB and a fellowship from the Dr Heinrich Kircher-Stiftung to SEL as well as the Austrian Science Fund (FWF) to AV.

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Authors and Affiliations

  1. Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany

    S E Lindner, M Wissler, P Brauns-Schubert, F Preiss, C Borner & U Maurer

  2. Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany

    S E Lindner, P Brauns-Schubert & F Preiss

  3. Department of Molecular Hematology, Center for Clinical Research, University Hospital, Freiburg, Germany

    A Gründer & H L Pahl

  4. Institute of Pathology, University Medical Centre Freiburg, Freiburg, Germany

    K Aumann

  5. Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria

    E Ottina, L Peintner, S Herzog & A Villunger

  6. Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany

    P Brauns-Schubert, F Preiss, C Borner & U Maurer

  7. BIOSS, Centre for Biological Signaling Studies, Freiburg, Germany

    C Borner & U Maurer

  8. Institut Cochin, INSERM U1016/CNRS UMR 8104, Université Paris Descartes, Rue Méchain, Paris

    C Charvet

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  1. S E Lindner
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  11. C Charvet
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Correspondence to U Maurer.

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Lindner, S., Wissler, M., Gründer, A. et al. Increased leukocyte survival and accelerated onset of lymphoma in the absence of MCL-1 S159-phosphorylation. Oncogene 33, 5221–5224 (2014). https://doi.org/10.1038/onc.2013.469

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