NF-­‐κB is a family of transcription factors responsible for the regulation of hundreds of genes controlling key cellular processes such as proliferation, apoptosis and inflammation. The activation of NF-­‐κB is an Achilles heel of many lymphoid malignancies. Therefore, a lot of effort is being made in investigating its regulatory mechanisms and exploring its therapeutic potentials. In this doctoral thesis, we have investigated the NF-­‐κB pathway in non-­‐Hodgkin lymphomas, with the aim of characterizing its expression and clinical impact in human lymphomas and identifying putative molecular targets able to interfere with its activation and lymphoma cell survival. Abnormal NF-­‐κB activation has been linked to Diffuse Large B-­‐cell Lymphoma (DLBCL) and has been described to play a key role in the pathogenesis of a specific molecular subtype of this malignancy, the ABC-­‐DLBCL. In the first part of this work, we evaluated the expression of NF-­‐κB by immunohistochemistry in a large series of DLBCL cases. The five different family members showed a heterogeneous and intricate expression pattern, but most remarkably, NF-­‐κB signaling was found to be a prominent feature not only in ABC-­‐DLBCL, but also in GCB-­‐ DLBCL, a subtype of DLBCL previously described to lack NF-­‐κB activation. Furthermore, c-­‐Rel expression was observed as a common feature in DLBCL and was able to identify a subset of patients with enhanced overall survival. Peripheral T-­‐cell lymphomas (PTCL) are highly aggressive tumors with a current lack of effective therapies, partly due to its unknown molecular pathology. In the second part of this work, we investigated the function of the NF-­‐κB–inducing kinase (NIK) in NF-­‐κB signaling and its potential as a molecular target in T-­‐cell lymphomas. We showed that the NF-­‐κB pathway was activated in a subset of PTCLs associated with poor overall survival. NIK was overexpressed in a number of PTCL cell lines and primary samples and a role for NIK as a critical regulator of both classical and alternative NF-­‐κB activation was unveiled. Using genetic silencing, we demonstrated a pivotal role for NIK in the survival of these tumor cells as NIK depletion led to a dramatic induction of apoptosis in NIK-­‐overexpressing cells. The knockdown of NIK led to a modulation of several key factors in cancer cell survival and apoptosis evasion and had also an impact on other important survival pathways, apart from NF-­‐κB, in PTCL pathogenesis. The results of this part of the study indicate that NIK could be a promising therapeutic target in these aggressive malignancies.

Tesis doctoral inédita, leída en Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 27/11/2013