PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers.

Autor:	Li Y; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania., Chitnis N; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania., Nakagawa H; Division of Gastroenterology, Departments of Medicine and Genetics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania., Kita Y; Department of Digestive Surgery, and Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima, Japan., Natsugoe S; Department of Digestive Surgery, and Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima, Japan., Yang Y; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina., Li Z; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina., Wasik M; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, Pennsylvania., Klein-Szanto AJ; Fox Chase Cancer Center, Philadelphia, Pennsylvania., Rustgi AK; Division of Gastroenterology, Departments of Medicine and Genetics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, Pennsylvania., Diehl JA; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. diehl@musc.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2015 Mar; Vol. 5 (3), pp. 288-303. Date of Electronic Publication: 2015 Jan 12.
DOI:	10.1158/2159-8290.CD-14-0625
Abstrakt:	Unlabelled: Protein arginine methyltransferase 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 proapoptotic and antiproliferative 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 specimens reveals a strong correlation between cyclin D1 overexpression and p53 methylation, supporting the biomedical relevance of this pathway. Significance: We have identified and functionally validated a crucial role for PRMT5 for the inhibition of p53-dependent tumor suppression in response to oncogenic insults. The requisite role for PRMT5 in the context of multiple lymphoma/leukemia oncogenic drivers suggests a molecular rationale for therapeutic development. (©2015 American Association for Cancer Research.)
Databáze:	MEDLINE
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