PRMT5 IS A POTENTIAL THERAPEUTIC VULNERABILITY IN BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic cancer that arises from malignant transformation of plasmacytoid dendritic cells (pDCs) and is predisposed to leukemic transformation. A recurrent feature of BPDCN is dysregulated MYC expression, which is associated with dependence on Protein arginine methyltransferase 5 (PRMT5). It was recently reported that BPDCN patient samples were enriched for a PRMT5 gene signature, suggesting a role for PRMT5 in BPDCN. In this thesis, the role and potential of PRMT5 as a therapeutic target in BPDCN, and how the expression of methyltransferase-like protein 3 (METTL3), a writer of m6A modification on RNA, determines BPDCN cells’ response to PRMT5 inhibition, was evaluated. Overall, the findings from this study have identified a new therapeutic target in BPDCN and uncovered a unique interconnection among PRMT5, METTL3 and interferon signaling pathway, which has not been reported in hematological malignancies like BPDCN.