Chemotherapy-induced cellular senescence promotes stemness of aggressive B-cell non-Hodgkin’s lymphoma via CCR7/ARHGAP18/IKBα signaling activation

• DOI: 10.1136/jitc-2024-009356
• Publication Date: 2025-01-07T19:21:07Z
• Authors: Jiyu Wang; Qianshan Tao; Keke Huang; Yangyang Wang; Linhui Hu; Anwen Ren; Huiping Wang; Yang Wan; Jinlan Li; Liuying Yi; Yanjie Ruan; Zhixiang Wanyan; Fan Wu; Zhimin Zhai; Chaohong Liu
• Keywords: Senescence

Background Resistance to existing therapies is a major cause of treatment failure in patients with refractory and relapsed B-cell non-Hodgkin’s lymphoma (r/r B-NHL). Therapy-induced senescence (TIS) one the most important mechanisms drug resistance. Methods This study used single-cell RNA sequencing analyze doxorubicin-induced senescent B-NHL cells. C-C chemokine receptor 7 (CCR7) expression aggressive was assessed using immunohistochemistry flow cytometry. Lentiviral transfection target CCR7 Raji SU-DHL-2 Protein localization visualized through immunofluorescence, while western blotting co-immunoprecipitation were protein interactions. Cell proliferation measured Counting Kit-8 assay, cells detected senescence-associated β-galactosidase staining. The stemness evaluated colony sphere formation assays. Transwell assays cell migration invasion. Finally, inhibitors GS143 Y27632 examine effect IKBα ARHGAP/RhoA inhibition on B-NHL-TIS. Results Here we identified distinct group TIS, composed memory population characterized by strong positive CCR7, which significantly elevated TIS compared normal proliferating autonomously populations. Additionally, upregulated r/r B-NHL, an independent prognostic factor high being strongly associated poor prognosis. In vitro results indicated that CCL21 induced invasion via blocking reduced these Furthermore, B-NHL-TIS regulated exhibited enhanced phenotypic functional features, including upregulation markers, increased colony-forming, invasive migratory capabilities. Mechanistically, reversed characteristics inhibiting activation ARHGAP18/IKBα signaling. Conclusions Together, promotes CCR7/ARHGAP18/IKBα signaling targeting CCR7/ARHGAP18 might overcome chemoresistance acquisition maintenance.