Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma

Xiong, S; Zhou, J; Tan, TK; Chung, T-H; Tan, TZ; Toh, SH-M; Tang, NXN; Jia, Y; See, YX; Fullwood, MJ; Sanda, T; Chng, W-J

Journal article

Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma

Abstract:: Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.Published versionThis work was supported by grants from the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative (MOH-000527-00 to W.J.C.), and the NMRC Clinician Scientist-Individual Research Grant (CS-IRG, CIRG19nov-0006 to W.J.C.; MOH-CIRG19nov-0004 to W.J.C.)

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Xiong, S., Zhou, J., Tan, T. K., Chung, T.-H., Tan, T. Z., Toh, S. H.-M., Tang, N. X. N., Jia, Y., See, Y. X., Fullwood, M. J., Sanda, T., & Chng, W.-J. (2024). Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma. Nature Communications, 15(1), 6810–6810.

MLA Style

Xiong, S, et al. “Super Enhancer Acquisition Drives Expression of Oncogenic PPP1R15B That Regulates Protein Homeostasis in Multiple Myeloma.” Nature Communications, vol. 15, no. 1, 2024, pp. 6810–10.

Chicago Style

Xiong, S, J Zhou, TK Tan, et al. 2024. “Super Enhancer Acquisition Drives Expression of Oncogenic PPP1R15B That Regulates Protein Homeostasis in Multiple Myeloma.” Nature Communications 15 (1): 6810–10.
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