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

作者：Xianghong Jin, Fujing Zhang, Huiwen He, Ziping Li, Junling Zhuang · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-205692 · 被引用次数：2 · 研究领域：Multiple Myeloma Research and Treatments、Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways

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 ...