Disrupting myddosome assembly in diffuse large B‑cell lymphoma cells using the MYD88 dimerization inhibitor ST2825

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkins lymphoma, is classified into germinal center and activated B cell (ABC) subtypes. The myeloid differentiation primary response gene 88 (MYD88) L265P mutation is the most prevalent oncogenic mutation among patients with ABC DLBCL, the subtype that has the more inferior outcome. MYD88 oligomerization driven by the L265P mutant augments myddosome assembly and triggers the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, highlighting MYD88 oligomerization as a potential therapeutic target for this malignancy. The synthetic peptidomimetic compound ST2825, which has previously been used as an anti-inflammatory agent, has been reported to inhibit MYD88 dimerization. In the present study, the anticancer effects of ST2825 were investigated using L265P-expressing ABC DLBCL cell lines. Using confocal microscopy and high-molecular-weight fraction experiments, it was revealed that L265P-associated myddosome assembly was disrupted by ST2825. The results also revealed that disrupting myddosome assembly promoted the death of ABC DLBCL cells harboring the L265P mutation, as well as downregulating survival signals, including the inhibition of NF-κB and the suppression of IL-10 and interferon-β production. Further co-immunoprecipitation studies demonstrated that MYD88 bound to BTK in L265P-DLBCL cells, and that this binding was abrogated following ST2825 treatment. Furthermore, the combination of myddosome-assembly disruption and BTK or BCL-2 signaling inhibition led to synergistic ABC DLBCL cell death, and more robust inhibition of NF-κB activity or increased apoptosis, respectively. The results of the present study provide evidence that the synthetic peptidomimetic compound ST2825, which targets myddosome assembly, may serve as a pharmacological inhibitor. ST2825 has the potential for clinical use in patients with L265P DLBCL, and other B-cell neoplasms driven by activated MYD88 signaling.

Downregulation of Inflammatory Cytokine Release from IL-1β and LPS-Stimulated PBMC Orchestrated by ST2825, a MyD88 Dimerisation Inhibitor

“…Furthermore, a weakness of this study was not to measure cell viability after stimulation with ST2825. Differences (that were not statistically significant) have been previously reported for ST2825 in other studies at 10, 20 or 30 μM on cell viability [ 19 , 20 , 58 ]. Our study used PBMC, reduction on specific PBMC subpopulations might contribute to the behaviour observed on these inflammatory cytokines.…”

“…Another study performed in healthy human articular chondrocytes reported decreased MAP kinase (MAPK) activation after MyD88 dimerisation inhibition and IL-1β stimulation [ 57 ]. An interesting study conducted by Wang et al (2019) previously reported that ST2825 decreases the expression of several molecules involved in the Myddosome formation, such as phosphorylated BTK and IκB, along with the decreased secretion of IL-10 and IFN-β from B-cell lymphoma cell lines [ 58 ]. In our study, IL-10 release decreases on both IL-1β and LPS-stimulated PBMC treated with ST2825; nonetheless, the effect was not statistically significant.…”

Identification of PLA2G7 as a novel biomarker of diffuse large B cell lymphoma

“…DLBCL is a common and highly heterogeneous form of NHL associated with high morbidity and mortality rates [ 26 ]. While roughly half of DLBCL cases can be cured via standard chemotherapy, treated relapsed or refractory DLBCL remains challenging [ 27 ]. It is thus essential that prognostic and diagnostic biomarkers of DLBCL be identified in order to guide patient detection and treatment.…”

Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression

“…Notably, NLRP3 is associated to myocardial injuries, atherosclerosis and diabetes mellitus (104); Sunitinib, through the induction of iROS and lipid peroxidation, activated MyD88 and NLRP3 increasing inflammation and pro-fibrotic state in cultured cells; notably, treatment with polydatin combined to sunitinib reduced the magnitude of these effects as well as the expression of MyD88 and NLRP3 in a concentration dependent fashion. Myddosome and inflammasome activates expression and release of cytokines, chemokines and growth factors involved in cell death, fibrosis, chemoresistance and apoptosis (105). IL-1b, IL-6, IL-8 and IL-18 reduces mitochondrial metabolism, calcium homeostasis and viability of cardiomyocytes, fibroblasts and pericardial cells (106,107).…”