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Background    The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma (r/r B-NHL) is resistance to current therapies, and therapy-induced senescence (TIS) stands out as a crucial mechanism contributing to tumor drug resistance. Here, we analyzed  SENEX /Rho GTPase Activating Protein 18 (ARHGAP18) expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients, investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods    Raji cells were transfected with the human  SENEX  shRNA recombinant lentiviral vector (Sh- SENEX ) and the empty vector negative (NC) to construct a stable transfection cell line with knockdown of  SENEX . Effect of  SENEX -silencing on B-NHL-TIS formation, cell function and cell cycle-related pathways was analyzed. Using doxorubicin (DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6 (CDK4/6) inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.  SENEX  expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR, and the correlation between its expression and clinical indicators were evaluated.Results    The downregulation of  SENEX  expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation, collectively suppressing the formation of TIS in B-NHL. Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing  SENEX  on B-NHL cell cycle regulation and senescence. The expression levels of  SENEX  were notably elevated in B-NHL patients compared to healthy controls, and Elevated expression levels of  SENEX  were associated with poor prognosis of B-NHL patients.ConclusionsSENEX  enhances apoptosis resistance in B-NHL by inhibiting CDK4/6, thereby preventing G1-S phase transition and promoting TIS formation.

SENEX -mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma