Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma

Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma

Haematologica

10.3324/haematol.2023.283467

https://haematologica.org/article/view/haematol.2023.283467

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

21 December 2023

Chong, P. S. Y., Chooi, J. Y., Lim, S. L. J., Chung, T.-H., Brunmeir, R., Leow, A. C. Y., Toh, S. H. M., Balan, K., Azaman, M. I. B., Wu, Z., Subramaniam, N., Vardy, L. A., & Chng, W.-J. (2023). Epigenetic dysregulation of eukaryotic initiation factor 3 subunit E (eIF3E) by lysine methyltransferase REIIBP confers a pro-inflammatory phenotype in t(4;14) myeloma. Haematologica. https://doi.org/10.3324/haematol.2023.283467

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 microRNAs by EZH2 in a Dicer-dependent manner, exemplifying a role of REIIBP in SET-mediated H3K27me3. ChIP-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 (BCR)-independent activation of BTK and driving NFĸB-mediated production of cytokines such as IL-6. Activation of this pathway is targetable using Ibrutinib and partially mitigated bortezomib resistance in an 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 coexistence of different NSD2 isoforms induced diversified oncogenic programs that should be considered in the strategies for t(4;14)-targeted therapy.

Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

WJC is supported by the National Medical Research Council via the Singapore Translational Research (STaR) Investigatorship. This research was partly supported by the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centers of Excellence initiative as well as the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Academic Research Fund Tier 3 grants, grant no. MOE2014-T3-1-006

Copyright (c) 2024 Ferrata Storti Foundation Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

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https://doi.org/10.3324/haematol.2023.283467