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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274078 | GEO | 2025/06/30

REPOSITORIES: GEO

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Project description:Multiple myeloma (MM) ranks the second most prevalent haematological malignancy globally. Despite advancements in managing MM, it remains incurable due to the high genetic heterogeneity leading to treatment resistance and disease severity. One key drug resistance associated signalling pathway often hyperactivated in MM patients is the non-canonical NF- κB/p52 pathway. Additionally, dysregulated expression of various oncogenic long non-coding RNAs (lncRNAs) have been observed in MM. This study aims to examine the potential link between ncNF-κB activation and dysregulated lncRNA expression controlling the chemoresistance and oncogenic progression of MM. Using mutant MM cell lines as model system and omics data from MM patients, we identified a novel p52 regulated lncRNA enriched in high-risk MM patients. The lncRNA termed PLUM (PRC2 associated LncRNA regulating UPR in MM) is found to interact directly with PRC2 complex to mediate myeloma progression and chemoresistance. RACE (Rapid amplification of cDNA ends) analysis revealed PLUM exists in three main isoforms in drug resistant multiple myeloma cell lines (MMCLs), comprising 8 exons without coding potential. Functionally, PLUM exerts its oncogenic and drug resistance properties in vivo and in vitro via the activation of unfolded protein response (UPR) pathway. This is consistent with its elevated expression in VRd (Bortezomib- Lenalidomide-Dexamethasone) non-responsive MM patients. PLUM localizes predominantly in the nucleus where it interacts directly with the disordered region of EZH2 (489-494 aa residues) to facilitate formation of the PRC2 complex and EZH2 activity. Disruption of this interaction using steric antisense oligonucleotides (ASOs) re-sensitized MMCLs to drug treatment in vitro and in vivo, correlating with the loss of EZH2 H3K27 trimethylation activity and PRC2 complex stability. Finally, we demonstrate that PLUM-EZH2 regulates the expression of tumour suppressor genes, FOXO3 and ZFP36, to activate the UPR pathway and promote chemoresistance in MM. These findings indicate that ncNF-κB pathway regulated lncRNA PLUM is oncogenic, acting through the PRC2/FOXO3/ZFP36 axis to confer chemoresistance in MM.

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

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