Loss of METTL3 Attenuates Blastic Plasmacytoid Dendritic Cell Neoplasm Response to PRMT5 Inhibition via IFN Signalling

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with poor clinical outcomes. Dysregulated MYC expression, which is associated with protein arginine methyltransferase 5 (PRMT5) dependency, is a recurrent feature of BPDCN. Although recent studies have reported a PRMT5 gene signature in BPDCN patient samples, the role of PRMT5 in BPDCN remains unexplored. Here, we demonstrate that BPDCN is highly sensitive to PRMT5 inhibition. Consistent with the upregulation of PRMT5 in BPDCN, we show that pharmacological inhibition (GSK3326595) of PRMT5 inhibits growth of the patient-derived BPDCN cell line CAL-1, in vitro and mitigated tumour progression in our mouse xenograft model. Interestingly, RNA-sequencing analysis revealed that PRMT5 inhibition increases intron retention in several key RNA methylation genes, including METTL3, which was accompanied by a dose-dependent decrease in METTL3 expression. Notably, METTL3's function of cellular m6A RNA modification was also affected by PRMT5 inhibition in CAL-1 cells. Intriguingly, METTL3 depletion in CAL-1 caused a significant increase in interferon signalling which was further elevated upon PRMT5 inhibition. Importantly, we discovered that this increase in interferon signalling attenuated the sensitivity of METTL3-depleted CAL-1 cells to PRMT5 inhibition. Correspondingly, stimulation of interferon signalling via TLR7 agonists weakened CAL-1 cells' sensitivity to PRMT5 inhibition. Overall, our findings implicate PRMT5 as a therapeutic target in BPDCN and provide insight into the involvement of METTL3 and interferon pathway in regulating response to

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S8664 Pemrametostat (GSK3326595) Pemrametostat (GSK3326595, EPZ015938) is an orally active, potent and selective inhibitor of protein arginine methyltransferase 5 (PRMT5) and potently inhibits tumor growth in vitro and in vivo in animal models.

Related Targets

Histone Methyltransferase PRMT