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The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence

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Abstract

Mutations leading to aberrant cytoplasmic localization of Nucleophosmin 1 (NPM1) have been recently identified as the most frequent genetic alteration in acute myelogenous leukemia. However, the oncogenic potential of this nucleophosmin mutant (NPMc+) has never been established, which casts doubt on its role in leukemogenesis. By performing classical transformation assays, we find that NPMc+, but not wild-type NPM, cooperates specifically with adenovirus E1A to transform primary mouse embryonic fibroblasts in soft agar. We demonstrate that NPMc+ blocks the p19Arf (Arf) induction elicited by E1A. Surprisingly, however, we find that NPMc+ induces cellular senescence and that E1A is able to overcome this response. We propose a model whereby the NPMc+ pro-senescence activity needs to be evaded for oncogenic transformation, even though NPMc+ can concomitantly blunt the Arf/p53 pathway. These findings identify for the first time NPMc+ as an oncogene and shed new unexpected light on its mechanism of action.

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Acknowledgements

We thank Dr G Gilliland for providing us the MSCV Flt3-ITD plasmid and Dr B Falini for the NPMc+ polyclonal antibody. We are grateful to C Nardella, Z Chen and H Lin and all members of PPP laboratory for discussions and critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Pathology, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    K Cheng, S Grisendi, J G Clohessy, S Majid, R Bernardi, P Sportoletti & P P Pandolfi

  2. Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY, USA

    K Cheng

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  1. K Cheng
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  2. S Grisendi
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  3. J G Clohessy
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  4. S Majid
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  5. R Bernardi
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  6. P Sportoletti
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  7. P P Pandolfi
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Correspondence to P P Pandolfi.

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

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Cheng, K., Grisendi, S., Clohessy, J. et al. The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence. Oncogene 26, 7391–7400 (2007). https://doi.org/10.1038/sj.onc.1210549

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  • DOI: https://doi.org/10.1038/sj.onc.1210549

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