2. Academic Validation
  3. Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma

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

  • Nat Commun. 2024 Aug 9;15(1):6810. doi: 10.1038/s41467-024-50910-z.
Sinan Xiong 1 2,  Jianbiao Zhou 3 4 5,  Tze King Tan 2,  Tae-Hoon Chung 2,  Tuan Zea Tan 2,  Sabrina Hui-Min Toh 2,  Nicole Xin Ning Tang 2,  Yunlu Jia 6,  Yi Xiang See 2,  Melissa Jane Fullwood 2 7 8 9,  Takaomi Sanda 1 2,  Wee-Joo Chng 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csizjb@nus.edu.sg.
  • 4 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. csizjb@nus.edu.sg.
  • 5 NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. csizjb@nus.edu.sg.
  • 6 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
  • 7 NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 8 School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
  • 9 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
  • 10 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. mdccwj@nus.edu.sg.
  • 11 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. mdccwj@nus.edu.sg.
  • 12 NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. mdccwj@nus.edu.sg.
  • 13 Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Health System (NUHS), Singapore, Singapore. mdccwj@nus.edu.sg.
PMID: 39122682 DOI: 10.1038/s41467-024-50910-z
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.

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