The Clinical Significance of Activated p-AKT Expression in Peripheral T-cell Lymphoma

摘要

Background: The oncogenic PI3K/serine-threonine kinase (PI3K/AKT) pathway is a downstream pathway of B-cell receptor (BCR) signaling pathway and plays a crucial role in the pathogenesis of B-cell lymphoma. However, there have been preclinical data showing PI3K/AKT pathway activation in T-cell lymphoma, with in different mechanisms from those in B-cell lymphoma. In this study, we investigated the impact of p-AKT expression on clinical outcomes of peripheral T-cell lymphoma (PTCL). Materials and Methods: We analyzed 63 patients with PTCL [PTCL-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL) or extranodal natural kiler T-cell lymphoma (NKTCL)]. To define the clinical implications of p-AKT expression in PTCL, we calculated arbitrary units (AUs) by multiplying the intensity and the proportion of p-AKT expression. Results: Based on a cutoff value of the upper limit of the third quartile (Q3) of the AU, 12 patients were classified into the high p-AKT group, while the remaining 51 patients were classified into the low p-AKT group. The overall response rate to frontline chemotherapy was significantly lower in the high p-AKT group than in the low p-AKT group (20.0% vs. 71.1%, p=0.004). The high p-AKT group showed substantially worse overall survival (OS) (median OS=2.3 vs. 25.2 months, p<0.001) and progression-free survival (PFS) (median PFS=1.6 vs. 8.8 months, p<0.001) compared with the low p-AKT group. Multivariate analysis showed that high p-AKT expression remained a significant independent poor prognostic factor for OS (hazard ratio (HR)=7.0; 95% confidence interval (CI)=3.0-16.6; p<0.001) and PFS (HR=6.8; 95% CI=3.0-15.2; p<0.001). Conclusion: PTCL patients with high p-AKT expression showed aggressive clinical courses with significantly worse OS and PFS and a poor chemotherapy response rate. We suggest that targeting the PI3K/AKT pathway may be a promising therapeutic strategy for PTCL.