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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.
The role of chromatin rewiring of regulatory elements in multiple myeloma (MM) remains poorly understood. Here, the authors identify a super-enhancer driven gene, PPP1R15B whose perturbation confers vulnerability in MM cells and suggest it as a therapeutic target.
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1 National University of Singapore, Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431)
2 National University of Singapore, Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431)
3 National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431)
4 Zhejiang University, Department of Surgical Oncology, Sir Run Run Shaw Hospital, Hangzhou, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X)
5 National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); Nanyang Technological University, School of Biological Sciences, Singapore, Singapore (GRID:grid.59025.3b) (ISNI:0000 0001 2224 0361); Agency for Science, Technology and Research, Institute of Molecular and Cell Biology, Singapore, Singapore (GRID:grid.418812.6) (ISNI:0000 0004 0620 9243)
6 National University of Singapore, Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, Cancer Science Institute of Singapore, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University of Singapore, NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, Singapore, Singapore (GRID:grid.4280.e) (ISNI:0000 0001 2180 6431); National University Health System (NUHS), Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), Singapore, Singapore (GRID:grid.410759.e) (ISNI:0000 0004 0451 6143)