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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)7391-7400
Number of pages10
JournalOncogene
Volume26
Issue number53
DOIs
Publication statusPublished - Nov 22 2007

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Cell Aging
Oncogenes
Leukemia
Adenoviridae
Acute Myeloid Leukemia
Agar
Fibroblasts
Mutation
nucleophosmin

Keywords

  • Arf
  • Cell transformation
  • E1A
  • NPMc+
  • Senescence

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions : Arf inactivation and induction of cellular senescence. / Cheng, K.; Grisendi, S.; Clohessy, J. G.; Majid, S.; Bernardi, R.; Sportoletti, P.; Pandolfi, P. P.

In: Oncogene, Vol. 26, No. 53, 22.11.2007, p. 7391-7400.

Research output: Contribution to journalArticle

Cheng, K. ; Grisendi, S. ; Clohessy, J. G. ; Majid, S. ; Bernardi, R. ; Sportoletti, P. ; Pandolfi, P. P. / The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions : Arf inactivation and induction of cellular senescence. In: Oncogene. 2007 ; Vol. 26, No. 53. pp. 7391-7400.
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