ST2825, independent of MyD88, induces reactive oxygen species-dependent apoptosis in multiple myeloma cells

Myeloid differentiation factor 88 (MyD88), which is a key regulator of nuclear factor kappa B (NF -KB), plays an important role in tumorigenesis in lymphoid malignancies such as Waldenstrom's macroglobulinemia (WM). However, its biological function in multiple myeloma (MM), which is a malignant plasma cell disorder like WM, remains unexplored. In this article, we first demonstrated that higher expression MyD88 was significantly correlated with poor survival in patients with MM using multiple publicly available datasets. Interestingly, bioinformatic analysis also revealed that MyD88 gene alteration, which is recognized in nearly 80% of patients with WM, was extremely rare in MM. In addition, ST2825 (a specific inhibitor of MyD88) suppressed cell growth followed by apoptosis. Furthermore, ST2825 induced intracellular reactive oxygen species (ROS) in MM cells, and N-acetyl-L-cysteine, which is known as a ROS scavenger, significantly decreased the number of apoptotic MM cells evoked by ST2825 treatment. Taken together, our results indicated that ST2825 leads to ROS-dependent apoptosis in MM cells and could be an attractive therapeutic candidate for patients with MM. By highlighting the pathological mechanism of MyD88 in MM, this study also provides novel treatment strategies to conquer MM.