Therapeutic Strategy Under Study in Myeloma Focuses on Telomere Stability

By: Joshua D. Madera, MS
Posted: Wednesday, May 10, 2023

Investigative efforts directed at developing pharmacotherapy for patients with multiple myeloma may have identified a suitable target, according to a study published in the Journal of Experimental & Clinical Cancer Research. Targeting the molecule hit 17, which is responsible for stabilization within the telomeric repeat-containing RNA (TERRA) transcripts, may serve as a novel strategy to improve outcomes for this patient population, suggested Maria Teresa Di Martino, PhD, of Magna Graecia University, Catanzaro, Italy, and colleagues.

“Our data show that multiple myeloma cell lines were more susceptible to treatment with hit 17 than normal cells and expressed lower TERRA levels as compared to normal cells. We can hypothesize that the difference in susceptibility to hit 17 treatments between normal and multiple myeloma cells can be partly due to intrinsic characteristics of tumor cells such as the mutational landscape,” explained Dr. Di Martino and colleagues.

AMO-1, AMO-BZB, NCI-H929, and RPMI-8826 multiple myeloma cell lines were obtained and cultured in RPMI-1640 media. Cell proliferation and flow cytometry assays were used to assess the antiproliferative activity of hit 17 and apoptotic processes, respectively. Quantitative reverse transcriptase polymerase chain reaction and Western blotting were used to quantify gene and protein expression. In addition, chromatin immunoprecipitation was implemented to evaluate the effect of hit 17 on the telomeric structure. Furthermore, in vivo experimentation was conducted on AMO-1 and NCI-H929 xenograft models.

The study findings revealed that stabilization of the TERRA G quadruplex led to telomeric repeat-binding factor 2 (TRF2) dissociating from telomeres. This, in turn, resulted in apoptotic death, cell-cycle arrest, proliferation block, and activation of the ATM-dependent DNA damage response. Moreover, when DNA damage occurred or TRF2 was lost, TERRA transcription was upregulated in cells. In multiple myeloma xenograft models, hit 17 demonstrated significant antitumor activity.

Disclosure: The study authors reported no conflicts of interest.

Journal of Experimental & Clinical Cancer Research

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