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

Wang,Xin; Tan,Yuan; Huang,Zhenglan; Huang,Ningshu; Gao,Miao; Zhou,Fangzhu; Hu,Jing; Feng,Wenli

doi:10.3892/or.2019.7282

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

Authors:
- Xin Wang
- Yuan Tan
- Zhenglan Huang
- Ningshu Huang
- Miao Gao
- Fangzhu Zhou
- Jing Hu
- Wenli Feng
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Affiliations: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by The Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Clinical Laboratory, Children's Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Clinical Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Clinical Laboratory, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400016, P.R. China
Published online on: August 19, 2019 https://doi.org/10.3892/or.2019.7282
Pages: 1755-1766
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diffuse large B‑cell lymphoma (DLBCL), the most common type of non‑Hodgkin's 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.

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