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

Sinan Xiong, Jianbiao Zhou (), Tze King Tan, Tae-Hoon Chung, Tuan Zea Tan, Sabrina Hui-Min Toh, Nicole Xin Ning Tang, Yunlu Jia, Yi Xiang See, Melissa Jane Fullwood, Takaomi Sanda and Wee-Joo Chng ()
Additional contact information
Sinan Xiong: National University of Singapore
Jianbiao Zhou: National University of Singapore
Tze King Tan: National University of Singapore
Tae-Hoon Chung: National University of Singapore
Tuan Zea Tan: National University of Singapore
Sabrina Hui-Min Toh: National University of Singapore
Nicole Xin Ning Tang: National University of Singapore
Yunlu Jia: Zhejiang University
Yi Xiang See: National University of Singapore
Melissa Jane Fullwood: National University of Singapore
Takaomi Sanda: National University of Singapore
Wee-Joo Chng: National University of Singapore

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-50910-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50910-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-50910-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().