Epigenetically mediated drug resistance in myeloma is coordinated by a myeloma-associated long non-coding RNA PLUM [RNA]

Multiple myeloma (MM) is the second most prevalent hematological malignancy that carries a poor prognosis. Despite significant advances in new treatments, most patients relapse due to the high genetic heterogeneity leading to treatment resistance. Recurrent mutations causing hyperactivation of the non-canonical NF-ĸB pathway are frequently enriched in relapsed, refractory MM patients, contributing to disease severity and drug resistance. Here, to identify NF-ĸB targets involved in chemoresistance, we combined multi-modal analysis of the NF-ĸB/p52 regulated myeloma epigenome with patient transcriptomics and uncovered a long non-coding RNA (lncRNA) linked to treatment resistant MM patients. The lncRNA termed PLUM is overexpressed in NF-ĸB+ high-risk MM subtypes and patients who are refractory to VRd (Bortezomib-Lenalidomide-Dexamethasone) treatment regimen. We reveal that PLUM interacts with Polycomb repressive complex 2 (PRC2) to regulate its stability and histone methyltransferase activity. Notably, PLUM binds to the disordered region of PRC2 subunit EZH2, modulating the expression of tumor suppressor genes, FOXO3 and ZFP36, to activate the unfolded protein response (UPR). Disruption of PLUM-EZH2 interaction using steric antisense oligonucleotides re-sensitized myeloma tumor cells to drug treatment, correlating with the loss of PRC2 stability and EZH2 H3K27 trimethylation activity. These findings indicate NF-ĸB/p52 regulated lncRNA, PLUM, modulates the myeloma epigenome by facilitating formation of PRC2 complex and EZH2 activity to mediate chemoresistance. Targeting specific PLUM-EZH2 interactions may represent a clinically important strategy for the treatment of relapsed, refractory MM. KMS-11 PLUM knock-down followed by RNA-seq (control/treated triplicates), H3K27me3 ChIP-seq (control/treated triplicates) and EZH2 ChIP-seq (endogenous duplicates)