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Although the clinical outcomes of diffuse large B‐cell lymphoma ( DLBCL ) have improved in the immunochemotherapy era, approximately one‐third of patients develop intractable disease. To improve clinical outcomes for these patients, it is important to identify those with poor prognosis prior to initial treatment in order to select optimal therapies. Here, we investigated the clinical and biological significance of  SPIB , an Ets family transcription factor linked to lymphomagenesis, in  DLBCL . We classified 134  DLBCL  patients into  SPIB  negative ( n  = 108) or  SPIB  positive ( n  = 26) groups by immunohistochemical staining.  SPIB  positive patients had a significantly worse treatment response and poor prognosis compared with  SPIB  negative patients. Multivariate analysis for patient survival indicated that  SPIB  expression was an independent poor prognostic factor for both progression free survival ( PFS ) and overall survival ( OS ) ( PFS , hazard ratio [ HR ] 2.65, 95% confidence interval [ CI ] 1.31–5.33,  P  = 0.006;  OS ,  HR  3.56, 95%  CI  1.43–8.91,  P  = 0.007). Subsequent analyses of the roles of  SPIB  expression in  DLBCL  pathogenesis revealed that  SPIB  expression in lymphoma cells resulted in resistance to the  BH 3‐mimetic  ABT ‐263 and contributed to apoptosis resistance via the  PI 3K‐ AKT  pathway. The inhibition of  AKT  phosphorylation re‐sensitized  SPIB  expressing lymphoma cells to  ABT ‐263‐induced cell death. Together, our data indicate that  SPIB  expression is a clinically novel poor prognostic factor in  DLBCL  that contributes to treatment resistance, at least in part, through an anti‐apoptotic mechanism.

SPIB is a novel prognostic factor in diffuse large B‐cell lymphoma that mediates apoptosis via the PI 3K‐ AKT pathway