YM155 Exerts Anti-Myeloma Effects Via Myc/BBC3 Signaling Pathway in Vitro

Background: Our previous studies have demonstrated a strong link between Myc rearrangement (Myc-R) and poor prognosis in newly diagnosed multiple myeloma (NDMM). The survivin inhibitor YM155, a novel small molecule, is currently under clinical investigation for aggressive B-cell lymphomas with Myc translocation. However, its effects on myeloma cells remain unclear.

Objectives: This study aims to explore the anti-myeloma mechanisms of YM155 in vitro through cell-based experiments.

Methods: In vitro, six MM cell lines (AMO-1, MM.1S, RPMI-8226, NCI-H929, U266, and KMS-11) were treated with YM155 to determine the IC50 using the CCK8 assay. Cell apoptosis was assessed by flow cytometry. RNA sequencing was conducted on MM.1S and RPMI-8226 cells to identify relevant regulatory pathways. Protein-protein interaction and transcription factor target prediction analyses were performed to predict interactions between proteins and the binding sites of Myc and its target genes. The identified regulatory pathways were validated using qPCR and Western blot (WB).

Results: The IC50 of YM155 in various MM cell lines ranged from 2.5 to 15 nM, which was similar to that of bortezomib. YM155 demonstrated a time- and dose-dependent inhibition of cell viability and induced apoptosis, significantly downregulating Myc expression at mRNA and protein levels. The combination of YM155 and bortezomib showed superior cytotoxicity compared to either agent alone, suggesting a synergistic effect. RNA sequencing indicated that Myc expression was suppressed and P53 signaling pathway was activated after YM155 treatment. This was confirmed by RT-qPCR and WB, which showed activation of pro-apoptotic protein BBC3 and inhibition of anti-apoptotic protein BCL2. JASPAR bioinformatic analysis predicted that Myc might inhibit BBC3 expression by binding its promoter region, thereby activating P53 pathway. Additionally, the IC50 of YM155 in bortezomib-resistant cells was 10.56 nM, similar to that in naïve cells.

Conclusion: YM155 exhibits in vitro anti-myeloma activity in a dose- and time-dependent manner and has a synergistic anti-tumor effect with bortezomib, reversing resistance to some extent. YM155 exerts its anti-myeloma effects by inhibiting Myc and upregulating BBC3 expression, which activates the P53 pathway. This provides its potential role for the treatment of high-risk/relapsed refractory MM.

Keywords: Multiple myeloma, high-risk, YM155, Myc inhibitor, drug resistance

No relevant conflicts of interest to declare.