TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Multiple myeloma (MM) exhibits high genomic instability, with telomere dysfunction contributing to genomic alterations.
• Telomeric repeat-containing RNA (TERRA) are long non-coding RNAs crucial for telomere stability via shelterin complex interaction.
• TERRA dysregulation is observed in various cancers, and a novel small molecule, hit 17, stabilizes TERRA secondary structures.

Purpose of the Study:

• To investigate the in vitro and in vivo anti-multiple myeloma (MM) activities of the small molecule hit 17.
• To elucidate the mechanism of action of hit 17 in MM cells, focusing on TERRA stabilization and its downstream effects.

Main Methods:

• Cell proliferation assays and flow cytometry were used to assess anti-proliferative and apoptotic effects of hit 17 in MM cell lines.
• Gene and protein expression were analyzed using RT-qPCR and western blotting, respectively.
• Chromatin immunoprecipitation and xenograft models were employed to evaluate effects on telomeric structure and in vivo anti-tumor activity.

Main Results:

• TERRA G4 stabilization by hit 17 led to telomeric repeat-binding factor 2 (TRF2) dissociation, activating DNA damage response, cell cycle arrest, and apoptosis in MM cells.
• TERRA transcription was upregulated following DNA damage and TRF2 loss.
• Transcriptome analysis revealed hit 17's impact on E2F, MYC, oxidative phosphorylation, and DNA repair pathways, with demonstrated anti-tumor activity in MM xenograft models.

Conclusions:

• Targeting TERRA with hit 17 presents a promising therapeutic strategy for multiple myeloma.
• Hit 17 demonstrates significant anti-MM activity through mechanisms involving TERRA stabilization and induction of cell death.