Down-regulation of cylindromatosis protein phosphorylation by BTK inhibitor promotes apoptosis of non-GCB-diffuse large B-cell lymphoma

摘要: Background Non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB-DLBCL) has worse clinical outcome than GCB-DLBCL, and some relapsed/refractory non-GCB-DLBCL (R/R non-GCB-DLBCL) are even resistant to CD20 monoclonal antibody (rituximab). Bruton's tyrosine kinase inhibitors (BTKis) new drugs for lymphoma. BTKis can promote apoptosis of DLBCL by inactivating nuclear transcription factor κB (NFκB) signaling pathway. Cylindromatosis (CYLD) is a tumor suppressor ubiquitinase. CYLD inactivate NFκB pathway through ubiquitination regulate the hematological tumors. The be regulated phosphorylation, suggesting that regulation phosphorylation potential mechanism Therefore, we hypothesized could regulating CYLD, especially in rituximab cases, proved this hypothesis both vivo vitro experiments. Methods baseline expression levels patients cell lines were detected Western Blotting. treated with BTKis, induced treatment was blotting, viability assay Annexin V assay. To verify whether effect on non-GCN-DLBCL cells dependent, knocked down lentiviral shRNAs. non-GCB-DLBCL, xeograft model generated inoculation escalation drug concentrations, respectively. Results down-regulating phosphorylationin non xenograft mouse model, rituximab-resistant cells, enhanced rituximab. Knocking-down reversed which BTKis. CYLD-dependent including cells. Conclusions present results indicated therapeutic target cases.