Oncogene induced senescence (OIS) is a barrier for tumour 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 tumour-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 due to activation of the p16INK4a/pRb tumour-suppressive pathway. Analysis of NPM-ALK lymphomagenesis in transgenic mice showed p16INK4a-dependent accumulation of senescent cells in pre-malignant lesions and decreased tumour 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 tumours.
The lymphoma-associated NPM-ALK oncogene elicits a p16INKa/pRb-dependent tumour-suppressive pathway / P. Martinelli, P. Bonetti, C. Sironi, G. Pruneri, C. Fumagalli, P.R. Raviele, S. Volorio, S. Pileri, R. Chiarle, F.K. Mcduff, B.K. Tusi, S.D. Turner, G. Inghirami, P.G. Pelicci, E. Colombo. - In: BLOOD. - ISSN 0006-4971. - 117:24(2011), pp. 6617-6626.
|Titolo:||The lymphoma-associated NPM-ALK oncogene elicits a p16INKa/pRb-dependent tumour-suppressive pathway|
|Parole Chiave:||Large-cell lymphoma; induced senescence; INK4A-ARF locus; gene-transfer; P53; P16(INK4A); mice; nucleophosmin; activation; stability|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1182/blood-2010-08-301135|
|Appare nelle tipologie:||01 - Articolo su periodico|