SMARCA2 is a novel interactor of NSD2 and regulates pro-metastatic PTP4A3 through chromatin remodeling in t(4;14) multiple myeloma.

NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass-spectrometry, we demonstrate a novel role of NSD2 in chromatin remodelling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was non-canonical and independent of the SWI/SNF complex. RNA-sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2-SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened.