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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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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DOI: https://doi.org/10.1038/onc.2013.469
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