HRP2-MINA complex reprograms t(4;14) multiple myeloma epigenome to dictate chemosensitivity to proteasome inhibitors [RNA-Seq]

Depletion of HRP2 induced remarkable resistance to PIs induced apoptosis of MM cells in vitro and in vivo, and suppressed expression of HRP2 was observed in bortezomib-resistant (BR) MM cells. Notably, HRP2 altered chemosensitivity more obviously in MM cells with t(4;14) translocation, and much remarkable resistant to PIs than other reagents. Moreover, HRP2 abolition of HRP2 augmented H3K27me3 modification, consequentially intensifying transcriptome alteration prone to cell survival and restriction of endoplasmic reticulum (ER) stress. Mechanistically, HRP2 recognized H3K36me2 and recruited the histone demethylases MYC-induced nuclear antigen (MINA) to degrade H3K27me3, released suppression on genes responsible for drug resistance, such as ATF3 and NR4A1. Thus, an EZH2 inhibitor, tazemetostat, synergistically sensitized anti-MM effect of bortezomib both in vitro and in vivo. Collectively, our study provides novel knowledge to understand the origination of chemoresistance in MM patients with t(4;14), and rationale for managing MM patients according to different genomic backgrounds. Non-target control and knockdown HRP2 knockdown LP-1 cells were divided into the following two groups : NC, HRP2 KD. And cells were harvested for gene expression profiling. Two replicates were performed.