The transcription factor NF-κB is a key regulator in many physiological processes, including innate and adaptative immune responses, inflammation and lymphoid organ development. NF-κB plays a crucial role in the development of B and T cells, by maintaining the cell death/survival equilibrium and therefore, constitutive activation of NF-κB is thought to contribute to the development and/or progression of B and T cell malignancies. The nfκb2 gene is frequently involved in chromosomal translocations associated with the development of various lymphomas and leukemias. These rearrangements all lead to the production of C-terminally truncated p100 proteins lacking variable portions of the ankyrin repeats domain, suggesting that this common feature may be involved in tumor development. However, whereas the oncogenic potential of such proteins is well established, the underlying mechanisms remain poorly understood. The aim of this work was to better understand these mechanisms by which such alterations contribute to lymphomagenesis. We then choose to investigate the functions of the protein Hut78 as representative of these p100ΔC mutants found in tumor cells. We identified mmp9 as a target gene of p52 and p52-producing NF-κB2 mutants and defined p52 as a key molecule for the invasive potential of lymphoma-derived cells harboring enhanced activity of the NF-κB alternative pathway. Moreover, we found that this p52/Hut78-mediated transcriptional induction of MMP9 involves the recruitment of MLL1 and MLL2 H3K4 histone methyltransferase complexes by p52 on the mmp9 gene promoter. Taken together, our results provide further insights into the oncogenic potential of the truncated p100 proteins, and by extension, will help to better understand how mutated IκB proteins contribute to deregulated NF-κB activities in haematological disorders.

Human immunodeficiency virus type 1 (HIV-1) is the causative virus for acquired immunodeficiency syndrome (AIDS). AIDS is characterized by chronic inflammation and reduction of CD4+ T-cells in the blood. This leads to the patient becoming immunocompromised and much more susceptible to disease in general. Different phenotypes in the progression of AIDS have been observed in patients in either progressing to AIDS faster as a Rapid Progressor (RP), or slower as a Long-Term Non-Progressor (LTNP). Researching elements that result in the LTNP phenotype is of interest as it has the potential to offer alternative treatments and therapies to those suffering from HIV and improve their quality of life. A separate genome wide association study into a population of LTNP patients had associated the R77Q mutation of viral protein R with the LTNP phenotype. Although this association has been controversial, recent work has shown that the R77Q mutation promotes apoptosis in a variety of cell lines compared to unmutated virus. However, the mechanisms behind the increase in apoptosis remain a place for further research. In this thesis, we attempted to elucidate some of the exact changes in gene expression between cells infected with the R77Q mutation and those without in the induction of apoptosis. We observed that apoptosis could be detected approximately 24 hours after infection via Annexin V staining, but there were no significant differences in the expression of genes within the first 24 hours. Furthermore, we observed 289 genes were then differentially expressed at 72 hours post infection. Analysis through SPIA revealed that the c-myc transcription factor pathway was activated in the R77Q infected cells and further analysis of the individual genes suggested less inflammatory signals in R77Q populations as well as an overall increase in antiapoptotic genes in WT infected cells. Exploration into the ANT1, Bax, and B-cl2 genes revealed that B-cl2 was upregulated in WT HIV infections and provided a degree of protection from apoptotic processes. Differences found in the expression of genes between R77Q and WT infected cells support the observation of increased apoptosis in R77Q infections and identify several targets for further research into the LTNP phenotype.