The Proteasome Component PSMD14 Drives Myelomagenesis through a Histone Deubiquitinase Activity

However, the molecular basis underlying the targeting of the 19S RP for myeloma therapy remains to be elucidated. Here we report that, unexpectedly, the 19S RP component PSMD14 is physically associated with the myeloma driver, NSD2 on chromatin independent of 19S RP.

We find that PSMD14 is a histone deubiquitinase acting on H2AK119, and that PSMD14-catalyzed H2AK119 deubiquitination facilitates NSD2-directed H3K36 di-methylation. Integrative genomic and epigenomic analyses reveal that the functional coordination between PSMD14 and NSD2 is associated with transcription activation of a cohort of genes including RELA that are critically involved in myelomagenesis. We show that RELA, in turn, transactivates PSMD14, establishing a positive feedback regulatory loop that explains well the long-reported clinical behaviours of myeloma.