PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers
Menée in vitro et in vivo, ainsi qu'à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un lymphome, cette étude met en évidence des mécanismes par lesquels, en coopération avec divers oncogènes, l'enzyme PRMT5 favorise le développement de la maladie
Protein arginine transferase 5(PRMT5) has been implicated as a key modulator of lymphomagenesis. Whether PRMT5 has overt oncogenic function in the context of leukemia/lymphoma and whether it represents a therapeutic target remains to be established. We demonstrate that inactivation of PRMT5 inhibits colony-forming activity by multiple oncogenic-drivers including cyclin D1, c-MYC, NOTCH1 and MLL-AF9. Furthermore, we demonstrate that PRMT5 overexpression specifically cooperates with cyclin D1 to drive lymphomagenesis in a mouse model revealing inherent neoplastic activity. Molecular analysis of lymphomas, revealed that arginine methylation of p53 selectively suppresses expression of crucial pro-apoptotic and anti-proliferative target genes thereby sustaining tumor cell self-renewal and proliferation and bypassing the need for the acquisition of inactivating p53 mutations. Critically, analysis of human tumor specimen reveal a strong correlation between cyclin D1 overexpression and p53 methylation supporting the biomedical relevance of this pathway.