The leukemia-associated cytoplasmic nucleophosmin mutant is an oncogene with paradoxical functions: Arf inactivation and induction of cellular senescence.
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 p19(Arf) (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.
Cheng
K
K
Cancer Biology and Genetics Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Grisendi
S
S
Clohessy
J G
JG
Majid
S
S
Bernardi
R
R
Sportoletti
P
P
Pandolfi
P P
PP
D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D009857:Oncogenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D017500:Adenovirus E1A Proteins; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin