ATF6 and pS6K as prognostic biomarkers in newly diagnosed diffuse large B-cell lymphoma

This study aimed to investigate the clinical and prognostic significance of activating transcription factor 6 (ATF6) and phosphorylated S6 kinase (pS6K) expression in newly diagnosed diffuse large B-cell lymphoma (DLBCL). We conducted a retrospective analysis of 107 DLBCL patients treated with the R-CHOP regimen at the Department of Hematology, Fourth Hospital of Hebei Medical University, between January 2019 and December 2022. Immunohistochemical staining was performed to evaluate ATF6 and pS6K expression levels in tumor tissues, followed by correlation analyses with clinical features and survival outcomes. Elevated ATF6 and pS6K expression levels were significantly correlated with advanced Ann Arbor stage (III-IV), presence of B symptoms, high International Prognostic Index (IPI) scores (≥ 2), extranodal involvement (> 1 site), peripheral blood lymphopenia (< 1.1 × 10⁹/L), and increased BCL-6 positivity. Survival curve analysis revealed that the overall survival (OS) and progression-free survival (PFS) rates in the high ATF6 (OS, 56.20% vs. 84.40%, P < 0.001; PFS, 41.10% vs. 77.00%, P < 0.001) and pS6K (OS, 52.30% vs. 79.60%, P < 0.001; PFS, 51.80% vs. 64.00%, P = 0.003) expression groups were significantly lower than those in the low expression groups. Multivariate analysis additionally confirmed that B symptoms (HR = 2.819, 95% CI: 1.131-7.027, P = 0.026), IPI scores of 2-3 (HR = 4.906, 95% CI: 1.501-16.042, P = 0.009), and high ATF6 expression (HR = 5.699, 95% CI: 1.223-26.552, P = 0.027) were risk factors for overall survival (OS), whereas the non-germinal center B cell (non-GCB) subtype (HR = 3.245, 95% CI: 1.080-9.748, P = 0.036), IPI scores of 2-3 (HR = 2.776, 95% CI: 1.156-6.662, P = 0.022), and high ATF6 expression (HR = 4.085, 95% CI: 1.418-11.768, P = 0.009) were identified as risk factors for progression-free survival (PFS). ATF6 and pS6K overexpression were strongly associated with aggressive clinicopathological features and closely associated with poor OS and PFS. These findings suggest that ATF6 and pS6K may serve as prognostic biomarkers, highlighting a potential avenue for risk stratification in newly diagnosed DLBCL patients.