The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway

Paola Martinelli, Paola Bonetti, Cristina Sironi, Giancarlo Pruneri, Caterina Fumagalli, Paola Rafaniello Raviele, Sara Volorio, Stefano Pileri, Roberto Chiarle, Fiona Kate Elizabeth McDuff, Betsabeh Khoramian Tusi, Suzanne D. Turner, Giorgio Inghirami, Pier Giuseppe Pelicci, Emanuela Colombo

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogene-induced senescence (OIS) is a barrier for tumor development. Oncogenedependent 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 histonedemethylase 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.

Original languageEnglish
Pages (from-to)6617-6626
Number of pages10
JournalBlood
Volume117
Issue number24
DOIs
Publication statusPublished - Jun 16 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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