The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway
| Autor: | Emanuela Colombo, Paola Bonetti, Paola Martinelli, Stefano Pileri, Suzanne D. Turner, Fiona Kate Elizabeth McDuff, Caterina Fumagalli, Betsabeh Khoramian Tusi, Giancarlo Pruneri, Sara Volorio, Cristina Sironi, Roberto Chiarle, Pier Giuseppe Pelicci, Giorgio Inghirami, Paola Rafaniello Raviele |
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| Přispěvatelé: | Martinelli P, Bonetti P, Sironi C, Pruneri G, Fumagalli C, Raviele PR, Volorio S, Pileri S, Chiarle R, McDuff FK, Tusi BK, Turner SD, Inghirami G, Pelicci PG, Colombo E. |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Senescence
Oncogene Proteins Lymphoma Oncogene Proteins Fusion DNA damage Immunology FUSION GENE NPM LYMPHOMA PROTEIN ARF ALK Biology Biochemistry Retinoblastoma Protein 03 medical and health sciences Mice 0302 clinical medicine hemic and lymphatic diseases Neoplasms medicine Animals Humans neoplasms Cells Cultured Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 030304 developmental biology Regulation of gene expression Mice Knockout 0303 health sciences Oncogene Tumor Suppressor Proteins Cell Biology Hematology Cell cycle Protein-Tyrosine Kinases medicine.disease Molecular biology Gene Expression Regulation Neoplastic Leukemia 030220 oncology & carcinogenesis Cancer research Signal Transduction |
| Zdroj: | Blood |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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