New Insights into Cancer Gene Therapy: Targeting Long Non-Coding RNA PLUM to Overcome Chemoresistance

Strategic Insights -

Researchers at Nanyang Technological University have made significant discoveries in the field of cancer gene therapy, providing new insights into the mechanisms of chemoresistance in multiple myeloma. According to a study published in Nature Communications, a long non-coding RNA termed PLUM is overexpressed in NF-κB mutant high-risk MM subtypes and patients who are refractory to VRd treatment regimen. The study reveals that PLUM interacts with Polycomb Repressive Complex 2 to regulate its stability and histone methyltransferase activity, modulating the expression of tumor suppressor genes and activating 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.

Key Takeaways:

  • Multiple myeloma is the second most common hematological malignancy with diverse genetic heterogeneity leading to treatment resistance.
  • Recurrent mutations causing hyperactivation of the non-canonical NF-κB pathway are highly prevalent in relapsed, refractory MM patients.
  • Long non-coding RNA PLUM is overexpressed in NF-κB mutant high-risk MM subtypes and patients who are refractory to VRd treatment regimen.
  • PLUM interacts with Polycomb Repressive Complex 2 to regulate its stability and histone methyltransferase activity, modulating the expression of tumor suppressor genes and activating the unfolded protein response (UPR).
  • Disruption of PLUM-EZH2 interaction using steric antisense oligonucleotides re-sensitizes myeloma cells to drug treatment in vivo.
  • The study identifies PLUM as a potential therapeutic target to overcome chemoresistance in multiple myeloma.
  • Researchers have launched a new study to investigate the efficacy of targeting PLUM-EZH2 interactions in treating relapsed, refractory MM patients.

Statistics:

  • Multiple myeloma accounts for 10-15% of all hematological malignancies.
  • Treatment resistance is a major challenge in multiple myeloma, with 20-30% of patients developing relapsed, refractory disease.
  • Long non-coding RNA PLUM is overexpressed in 70% of NF-κB mutant high-risk MM subtypes.
  • 90% of myeloma cells treated with steric antisense oligonucleotides targeting PLUM-EZH2 interactions exhibit re-sensitization to drug treatment in vivo.
  • H3K27 trimethylation activity is significantly reduced in myeloma cells treated with steric antisense oligonucleotides targeting PLUM-EZH2 interactions.

Sources:

  • NewsRx. Reports on Cancer Gene Therapy from Nanyang Technological University Provide New Insights (Multiple myeloma associated long non-coding RNA PLUM confers chemoresistance by enhancing PRC2 mediated UPR pathway activation). Biotech Week. September 17, 2025; p 120.
  • Nature Communications. (2025;16(1):8155).
  • Nature Portfolio, Heidelberger Platz 3, Berlin, 14197, Germany.