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

Sep 24, 2026

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Multiple myeloma is a hematologic malignancy marked by high genomic instability, with telomere dysfunction as a key driver of acquired alterations. Telomeric repeat-containing RNA (TERRA) acts as a long non-coding RNA regulating telomere stability via shelterin interactions, and TERRA dysregulation has been noted across cancers. This study tests the small molecule hit 17, previously identified to stabilize TERRA structure, to evaluate its in vitro and in vivo anti-MM activity and mechanistic impact.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusion

Introduction and Background Concepts

Genomic instability in multiple myeloma

Telomere dysfunction and telomeric structure

TERRA transcripts and G-quadruplex biology

Scionti et al. J Exp Clin Cancer Res (2023) 42:71 [https://doi.org/10.1186/s13046-023-02633-0](https://doi.org/10.1186/s13046-023-02633-0) Journal of Experimental & Clinical Cancer Research RESEARCH Open Access TERRA G-quadruplex stabilization as a new therapeutic strategy for multiple myeloma Francesca Scionti1†, Giada Juli1†, Roberta Rocca 1,2, Nicoletta Polerà 1, Matteo Nadai3, Katia Grillone1, Daniele Caracciolo1, Caterina Riillo 1, Emanuela Altomare1, Serena Ascrizzi1, Basilio Caparello4, Maria Cerra4, Mariamena Arbitrio5, Sara N. Richter3, Anna Artese2,6, Stefano Alcaro2,6, Pierosandro Tagliaferri1, Pierfrancesco Tassone1*† and Maria Teresa Di Martino 1*† Abstract Background Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability, and telomere dysfunction is an important cause of acquired genomic alterations. Telomeric repeat-containing RNA (TERRA) transcripts are long non-coding RNAs involved in telomere stability through the interaction with shelterin complex. Dysregulation of TERRAs has been reported across several cancer types. We recently identified a small molecule, hit 17, which stabilizes the secondary structure of TERRA. In this study, we investigated in vitro and in vivo anti-MM activities of hit 17. Methods Anti-proliferative activity of hit 17 was evaluated in different MM cell lines by cell proliferation assay, and the apoptotic process was analyzed by flow cytometry. Gene and protein expressions were detected by RT-qPCR and western blotting, respectively. Microarray analysis was used to analyze the transcriptome profile. The effect of hit 17 on telomeric structure was evaluated by chromatin immunoprecipitation. Further evaluation in vivo was proceeded upon NCI-H929 and AMO-1 xenograft models. Results TERRA G4 stabilization induced in vitro dissociation of telomeric repeat‐binding factor 2 (TRF2) from telomeres leading to the activation of ATM-dependent DNA damage response, cell cycle arrest, proliferation block, and apoptotic death in MM cell lines. In addition, up-regulation of TERRA transcription was observed upon DNA damage and TRF2 loss. Transcriptome analysis followed by gene set enrichment analysis (GSEA) confirmed the involvement of the above-mentioned processes and other pathways such as E2F, MYC, oxidative phosphorylation, and DNA repair genes as early events following hit 17-induced TERRA stabilization. Moreover, hit 17 exerted anti-tumor activity against MM xenograft models. Conclusion Our findings provide evidence that targeting TERRA by hit 17 could represent a promising strategy for a novel therapeutic approach to MM. Keywords Multiple myeloma, TERRA, Telomere dysfunction, TRF2, Small molecules, DNA damage, Genomic instability, Long non-coding RNA, lncRNAs | †Francesca Scionti and Giada Juli are co-first authors. | | --- | | †Pierfrancesco Tassone and Maria Teresa Di Martino are co-last authors. | *Correspondence: Pierfrancesco Tassone[tassone@unicz.it](tassone@unicz.it)[ ](tassone@unicz.it)Maria Teresa Di Martino [teresadm@unicz.it](teresadm@unicz.it) Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, v

FAQs

What is the role of TERRA in telomere stability for multiple myeloma?

TERRA transcripts are long non-coding RNAs involved in telomere stability through interactions with the shelterin complex, particularly via TRF2-related functions.

How does hit 17 affect TERRA and telomeric structure?

Hit 17 stabilizes the secondary structure of TERRA, inducing TERRA G4 stabilization that leads to TRF2 dissociation from telomeres and triggers downstream DNA damage responses.

What anti-tumor effects were observed after hit 17 treatment?

Hit 17 induced cell cycle arrest and proliferation block, promoted apoptotic death in multiple myeloma cell lines, and showed anti-tumor activity in MM xenograft models.

Sep 24, 2026

Uploaded by Finn