T-Cell Receptor Dependent and Independent NF-kappa B Activation is a Prognostic Marker and a Therapeutic Target in Peripheral T-cell Lymphoma Not Otherwise Specified

Abstract

Peripheral T-cell lymphomas not otherwise specified (PTCL/NOS) is the commonest subtype of PTCL. NF–kB related molecules have been found to be variably expressed in PTCL/NOS, suggesting a potential involvement of the NF–kB system in their pathogenesis. However, the actual contribution of NF–kB molecular programs to the PTCL/NOS landscape has not been investigated yet. In this study, we assessed in a large series of PTCL/NOS, the activation status of NF–kB programs and investigated the prognostic impact of such NF–kB expression. Moreover, we explored the possible role of NF–kB inhibitors. We studied the gene expression profiles of 180 PTCL cases and tested two different drugs, the IKK inhibitor BMS-345541 and the proteasome inhibitor Bortezomib, in four PTCL cell lines. We found that most cases (84%) presented with some degree of NF–kB activation, based on the expression of REL and RELA. Functionally, the latter was strictly related with TCR signaling activation, while REL was at least partially TCR independent. We also identified genes related with NF–kB activation in this setting that were mainly involved in cell proliferation and apoptosis inhibition. Further, by reverse engineering we defined the transcriptional network of both REL and RELA in PTCLs that only partially overlapped. On the clinical ground, we found that RELA expression was related to a significantly poorer overall survival, with similar trends for REL. However, most remarkably, when all the three genes were considered together, cases with at least one gene over-expressed, showed a dramatically inferior overall survival (28.67 vs. 56.018 months; p = 0.004). Finally, we showed that NF–kB pharmacological inhibition was associated with cell cycle arrest and cell death in NF–kB positive PTCL cells. In conclusion, we extensively explored NF–kB activation in PTCL/NOS, documenting its negative prognostic role. Further, we showed that NF–kB inhibition might represent a rational therapeutic approach in selected cases.