The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence.
Cheng, K 1,2; Grisendi, S 1; Clohessy, J G 1; Majid, S 1; Bernardi, R 1; Sportoletti, P 1; Pandolfi, P P 1
[Article]
Oncogene.
26(53):7391-7400, November 22, 2007.
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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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