Insight into the oncogenic potential of NF-kappaB2 truncated proteins through identification of their target genes

The transcription factor NF-κ;B is a key regulator in many physiological processes, including innate and adaptative immune responses, inflammation and lymphoid organ development. NF-κ;B 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-κ;B is thought to contribute to the development and/or progression of B and T cell malignancies. The nfκ;b2 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-κ;B2 mutants and defined p52 as a key molecule for the invasive potential of lymphoma-derived cells harboring enhanced activity of the NF-κ;B 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 Iκ;B proteins contribute to deregulated NF-κ;B activities in haematological disorders.