Supplementary Table S1. T cell receptor (TCR) Vβ repertoire usage in CD3+CD4+ T cells from tumor-bearing and non tumor-bearing mice. Supplementary Figure S1. Pancytopenia in D1T286A-reconstituted mice, immnuphenotype of PRMT5-reconstituted mice and TCR clonality of D1T286A+PRMT5 mice. Supplementary Figure S2 Phenotype of the D1T286A+PRMT5 lymphoma and the D1T286A and PRMT5 triggered lymphoma is 100% transplantable. Supplementary Figure S3. PRMT5 is required for leukemia driven by MLL-AF9. Supplementary Figure S4. Cyclin D1T286A triggers T/B-cell lymphoma in p53 dependent way. Supplementary Figure S5. Confirmation of Cyclin D1T286A/PRMT5 expression and p53me2 antibody. Supplementary Figure S6. Cyclin D1T286A/CDK4 phosphorylation of MEP50 increases PRMT5-dependent methylation of p53. Supplementary Figure S7. Effect of PRMT5 and D1T286A on the Apaf1, Cdkn1a, Bax and Pmaip1 promoters. Supplementary Figure S8. PRMT5 and/or H4R3 are elevated in primary human cancers.
ARTICLE 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.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. Cancer Discov; 5(3); 288–303. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 213
