title: The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway.
abstract: Oncogene-induced senescence (OIS) is a barrier for tumor development. Oncogene-dependent DNA damage and activation of the ARF/p53 pathway play a central role in OIS and, accordingly, ARF and p53 are frequently mutated in human cancer. A number of leukemia/lymphoma-initiating oncogenes, however, inhibit ARF/p53 and only infrequently select for ARF or p53 mutations, suggesting the involvement of other tumor-suppressive pathways. We report that NPM-ALK, the initiating oncogene of anaplastic large cell lymphomas (ALCLs), induces DNA damage and irreversibly arrests the cell cycle of primary fibroblasts and hematopoietic progenitors. This effect is associated with inhibition of p53 and is caused by activation of the p16INK4a/pRb tumor-suppressive pathway. Analysis of NPM-ALK lymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in premalignant lesions and decreased tumor latency in the absence of p16INK4a. Accordingly, human ALCLs showed no expression of either p16INK4a or pRb. Up-regulation of the histone-demethylase Jmjd3 and de-methylation at the p16INK4a promoter contributed to the effect of NPM-ALK on p16INK4a, which was transcriptionally regulated. These data demonstrate that p16INK4a/pRb may function as an alternative pathway of oncogene-induced senescence, and suggest that the reactivation of p16INK4a expression might be a novel strategy to restore the senescence program in some tumors.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Martinelli
authors.forename: Paola
authors.initials: P
authors.lastname: Bonetti
authors.forename: Cristina
authors.initials: C
authors.lastname: Sironi
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Pruneri
authors.forename: Caterina
authors.initials: C
authors.lastname: Fumagalli
authors.forename: Paola Rafaniello
authors.initials: PR
authors.lastname: Raviele
authors.forename: Sara
authors.initials: S
authors.lastname: Volorio
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
authors.forename: Fiona Kate Elizabeth
authors.initials: FK
authors.lastname: McDuff
authors.forename: Betsabeh Khoramian
authors.initials: BK
authors.lastname: Tusi
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Emanuela
authors.initials: E
authors.lastname: Colombo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D015514:Oncogene Proteins, Fusion; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases