Multiple myeloma associated long non-coding RNA PLUM confers chemoresistance by enhancing PRC2 mediated UPR pathway activation

Multiple myeloma (MM) is the second most common hematological malignancy that displays diverse genetic heterogeneity leading to treatment resistance. Recurrent mutations causing hyperactivation of the non-canonical NF-ĸB pathway are highly prevalent in relapsed, refractory MM patients, but the precise mechanisms driving chemoresistance are poorly understood. Here, we identify a long non-coding RNA termed PLUM, that is overexpressed in NF-ĸB mutant high-risk MM subtypes and patients who are refractory to VRd treatment regimen. Mechanistically, PLUM interacts with Polycomb Repressive Complex 2 to regulate its stability and histone methyltransferase activity, modulating the expression of tumor suppressor genes, FOXO3 and ZFP36, to activate the unfolded protein response (UPR). Importantly, disruption of PLUM-EZH2 interaction using steric antisense oligonucleotides re-sensitizes myeloma cells to drug treatment in vivo, correlating with the loss of PRC2 stability and H3K27 trimethylation activity. These findings indicate that PLUM facilitates formation of PRC2 complex and enhances EZH2 activity, modulating the myeloma epigenome to mediate chemoresistance. Hence, targeting PLUM-EZH2 interactions may represent a clinically potent strategy for the treatment of relapsed, refractory MM.