Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma
Phyllis S.Y. Chong,
Jing Yuan Chooi,
Sze Lynn Julia Lim,
Tae-Hoon Chung,
Reinhard Brunmeir,
Aaron Chung Yong Leow,
Sabrina Hui Min Toh,
Kalpnaa Balan,
Muhamad Irfan Bin Azaman,
Zhengwei Wu,
Nagavidya Subramaniam,
Leah A Vardy,
Wee-Joo Chng
Affiliations
Phyllis S.Y. Chong
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore
Jing Yuan Chooi
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
Sze Lynn Julia Lim
Cancer Science Institute of Singapore, National University of Singapore
Tae-Hoon Chung
Cancer Science Institute of Singapore, National University of Singapore
Reinhard Brunmeir
Cancer Science Institute of Singapore, National University of Singapore
Aaron Chung Yong Leow
Cancer Science Institute of Singapore, National University of Singapore
Sabrina Hui Min Toh
Cancer Science Institute of Singapore, National University of Singapore
Kalpnaa Balan
Cancer Science Institute of Singapore, National University of Singapore
Muhamad Irfan Bin Azaman
Cancer Science Institute of Singapore, National University of Singapore
Zhengwei Wu
Cancer Science Institute of Singapore, National University of Singapore, Singapore; Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
Nagavidya Subramaniam
A*STAR Skin Research Labs and Skin Research Institute of Singapore, A*STAR, Immunos, Singapore
Leah A Vardy
A*STAR Skin Research Labs and Skin Research Institute of Singapore, A*STAR, Immunos, Singapore
Wee-Joo Chng
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Hematology-Oncology, National University Cancer Institute of Singapore, National University Health System
REIIBP is a lysine methyltransferase aberrantly expressed through alternative promoter usage of NSD2 locus in t(4;14)-translocated multiple myeloma (MM). Clinically, t(4;14) translocation is an adverse prognostic factor found in approximately 15% of MM patients. The contribution of REIIBP relative to other NSD2 isoforms as a dependency gene in t(4;14)-translocated MM remains to be evaluated. Here, we demonstrated that despite homology with NSD2, REIIBP displayed distinct substrate specificity by preferentially catalyzing H3K4me3 and H3K27me3, with little activity on H3K36me2. Furthermore, REIIBP was regulated through microRNA by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. Chromatin immunoprecipitation sequencing revealed chromatin remodeling characterized by changes in genome-wide and loci-specific occupancy of these opposing histone marks, allowing a bidirectional regulation of its target genes. Transcriptomics indicated that REIIBP induced a pro-inflammatory gene signature through upregulation of TLR7, which in turn led to B-cell receptor-independent activation of BTK and driving NFkB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in a REIIBP xenograft model. Mechanistically, REIIBP upregulated TLR7 through eIF3E, and this relied on eIF3E RNA-binding function instead of its canonical protein synthesis activity, as demonstrated by direct binding to the 3’UTR of TLR7 mRNA. Altogether, we provided a rationale that co-existence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.