SUP-M2

Background

Multiple myeloma (MM) is a hematological malignancy with poorly understood chromatin rewiring. This study integrates H3K27ac ChIP-seq and HiChIP to map myeloma-associated super-enhancers (SEs). It identifies PPP1R15B as an SE-driven oncogene encoding a regulatory subunit of the eIF2α phosphatase complex. PPP1R15B silencing activates the pro-apoptotic eIF2α-ATF4-CHOP pathway and inhibits protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B with Raphin1 potentiates bortezomib's anti-myeloma effect, highlighting a promising therapeutic strategy targeting protein homeostasis.

Key Findings

Integrative analysis of H3K27ac ChIP-seq and HiChIP identified 223 gained super-enhancers (SEs) in multiple myeloma (MM), leading to a prioritized list of nine SE-associated genes. PPP1R15B was found to be overexpressed in MM and associated with poor survival. Its SE is activated by transcription factors CEBPB and YY1. PPP1R15B depletion inhibited cell proliferation, induced apoptosis, and suppressed global protein synthesis and immunoglobulin secretion. Mechanistically, PPP1R15B dephosphorylates eIF2α, suppressing pro-apoptotic UPR and activating mTORC1 signaling. In vivo, PPP1R15B knockdown prolonged survival in a xenograft model. Pharmacological inhibition with Raphin1 induced apoptosis in MM cells and synergized with bortezomib. These findings demonstrate that PPP1R15B is a critical regulator of protein homeostasis and a promising therapeutic target in MM.

Contribution

Creative Bioarray provided the anaplastic large cell lymphoma cell line SUP-M2 (Cat# CSC-C0518), which was used to assess the therapeutic potential of PPP1R15B inhibition in other cancer types. This contributed to demonstrating the broader applicability of targeting PPP1R15B beyond multiple myeloma.