Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma
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.
Authors
- Tuan Zea Tan (ORCID: https://orcid.org/0000-0001-6624-1593)
- Yunlu Jia (ORCID: https://orcid.org/0000-0003-2213-7561)
- Yi Xiang See (ORCID: https://orcid.org/0000-0001-6511-8833)
- Sinan Xiong (ORCID: https://orcid.org/0000-0003-3761-2505)
- Tae‐Hoon Chung (ORCID: https://orcid.org/0000-0003-1737-6322)
- Jianbiao Zhou (ORCID: https://orcid.org/0000-0002-5679-671X)
- Takaomi Sanda (ORCID: https://orcid.org/0000-0003-1621-4954)
- Wee Joo Chng (ORCID: https://orcid.org/0000-0003-2578-8335)
- Sabrina Hui Min Toh (ORCID: https://orcid.org/0009-0008-9206-2036)
- Tze King Tan (ORCID: https://orcid.org/0000-0003-1623-615X)
- Melissa J. Fullwood (ORCID: https://orcid.org/0000-0003-0321-7865)
- Nicole Xin Ning Tang (ORCID: https://orcid.org/0009-0006-2147-790X)
Institutions
- Agency for Science, Technology and Research (SG)
- National University of Singapore (SG)
- Nanyang Technological University (SG)
- Sir Run Run Shaw Hospital (CN)
- National University Cancer Institute, Singapore (SG)
- National University Health System (SG)
- Institute of Molecular and Cell Biology (SG)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1038/s41467-024-50910-z
- Citations
- 11
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.57
Funders
- National Research Foundation
- National University of Singapore
- National Research Foundation Singapore
- Ministry of Education - Singapore
- National Medical Research Council
- Cancer Science Institute of Singapore, National University of Singapore