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Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825
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 D...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775815/ https://www.ncbi.nlm.nih.gov/pubmed/31432184 http://dx.doi.org/10.3892/or.2019.7282 |
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author | Wang, Xin Tan, Yuan Huang, Zhenglan Huang, Ningshu Gao, Miao Zhou, Fangzhu Hu, Jing Feng, Wenli |
author_facet | Wang, Xin Tan, Yuan Huang, Zhenglan Huang, Ningshu Gao, Miao Zhou, Fangzhu Hu, Jing Feng, Wenli |
author_sort | Wang, Xin |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6775815 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-67758152019-10-10 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 Oncol Rep Articles 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. D.A. Spandidos 2019-11 2019-08-19 /pmc/articles/PMC6775815/ /pubmed/31432184 http://dx.doi.org/10.3892/or.2019.7282 Text en Copyright: © Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Wang, Xin Tan, Yuan Huang, Zhenglan Huang, Ningshu Gao, Miao Zhou, Fangzhu Hu, Jing Feng, Wenli Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825 |
title | Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825 |
title_full | Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825 |
title_fullStr | Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825 |
title_full_unstemmed | Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825 |
title_short | Disrupting myddosome assembly in diffuse large B-cell lymphoma cells using the MYD88 dimerization inhibitor ST2825 |
title_sort | disrupting myddosome assembly in diffuse large b-cell lymphoma cells using the myd88 dimerization inhibitor st2825 |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775815/ https://www.ncbi.nlm.nih.gov/pubmed/31432184 http://dx.doi.org/10.3892/or.2019.7282 |
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