Mechanisms of mature B-cell tumour pathogenesis and of the interplay between host-immunity and these tumours.

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The incidence of non-Hodgkin's lymphoma (NHL), the majority of which derived from mature B-cells, has virtually doubled in the last two decades in westernized countries. Although improved diagnosis, and AIDS associated lymphomas have contributed to this astonishing escalation of disease incidence, this contribution accounts for no more than 50% of the new cases. Amongst NHL's the Activated B-cell Diffuse Large B-cell Lymphoma (ABC-DLBCL) is the most aggressive and with the poorer clinical prognosis. Multiple Myeloma (MM) is a tumour derived from terminally differentiated mature B-cells (plasma cells) and ranks as the second most common haematological malignancy after NHL, and despite recent advances in chemotherapy it is still an incurable disease. Constitutive NF-kB activity, present in both these tumours interferes with the apoptotic effect of chemotherapy and may account for the poor response to treatment of patients with either ABC-DLBCL or MM. Using sophisticated genetic approaches that include conditional gain-of-function and/or loss-of-function in the mouse, I plan to develop bona-fide pre-clinical models of these diseases in an experimental setting that recapitulates human mature B-cell tumourigenesis as closely as currently possible. These models should prove invaluable for the elucidation of the mechanistic factors in the pathogenesis of these malignancies and provide critical information for the advancement of disease prevention and treatment. In addition to oncogenetic lesions, it has become increasingly clear that host immunity plays a fundamental role in tumour formation and progression. Cancer immune escape is an emerging "Hallmark of Cancer" and regulatory T-cells (Tregs) may play a key role in this context. However, although in solid tumours Tregs aid cancer immune escape their role in haematological malignancies remains controversial, warranting caution when attempting to extrapolate effective treatment strategies in solid tumours. I plan to determine the role of Treg cells in the initiation and progression of human ABC-DLBCL and MM, using the bona fide mouse models for these diseases described above. I expect that inter-species comparative oncogenomics of the tumours arising in mice with their human counterparts will lead to the identification of causative/driver genetic mutations, which could function as prognostic biomarkers and/or therapeutic targets. On other hand, a better understanding of Treg function in the context of haematological malignancies will provide insights on how and when to modulate their activity to stimulate the immune system to control tumour growth.