title: PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Chitnis
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Genetics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Department of Digestive Surgery, and Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kita
authors.affiliation: Department of Digestive Surgery, and Breast and Thyroid Surgery, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, Pennsylvania.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Wasik
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Andres J P
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. diehl@musc.edu.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001120:Arginine / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D020869:Gene Expression Profiling; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D051379:Mice; D009154:Mutation; D009857:Oncogenes; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001120:Arginine; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D011484:Protein-Arginine N-Methyltransferases; D016159:Tumor Suppressor Protein p53; C400529:PRMT5 protein, human; C478359:WDR77 protein, human; D014157:Transcription Factors