SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma. (Cancer Res, May 2021)

Phyllis S Y Chong # 1Jing Yuan Chooi # 2Julia S L Lim 2 3Sabrina Hui Min Toh 3Tuan Zea Tan 3Wee-Joo Chng 1 3 4


1Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3Cancer Science Institute of Singapore, National University of Singapore, Singapore.
4Department of Heamatology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.

#Contributed equally.


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 remodeling 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 noncanonical 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. SIGNIFICANCE: This study uncovers a novel, SWI/SNF-independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.

PMID: 33602783 DOI: 10.1158/0008-5472.CAN-20-2946