Abstract
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 BH3-mimetic ABT-263 and contributed to apoptosis resistance via the PI3K-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.