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

非霍奇金淋巴瘤（NHL）的发病率，其中大部分来自成熟的B细胞，在过去的二十年中在西方国家几乎翻了一番。尽管诊断的改进和艾滋病相关淋巴瘤导致了疾病发病率的惊人上升，但这种贡献不超过新病例的50%。在NHL中，活化B细胞弥漫性大B细胞淋巴瘤（ABC-DLBCL）是最具侵袭性的，临床预后较差。多发性骨髓瘤（MM）是一种来源于终末分化成熟B细胞（浆细胞）的肿瘤，是仅次于NHL的第二大常见血液恶性肿瘤，尽管最近化疗取得了进展，但它仍然是一种无法治愈的疾病。存在于这两种肿瘤中的组成性NF-kB活性干扰化疗的凋亡作用，并可能导致ABC-DLBCL或MM患者对治疗反应不良。使用复杂的遗传方法，包括小鼠中的条件性功能获得和/或功能丧失，我计划在实验环境中开发这些疾病的真正的临床前模型，尽可能接近地再现人类成熟B细胞肿瘤发生。这些模型应该证明是非常宝贵的阐明这些恶性肿瘤的发病机制的机制因素，并为疾病的预防和治疗的进步提供重要的信息。除了致癌病变，越来越清楚的是，宿主免疫在肿瘤的形成和发展中起着重要作用。癌症免疫逃逸是一种新兴的“癌症标志”，调节性T细胞（TCFs）可能在此背景下发挥关键作用。然而，尽管在实体瘤中，TCFs帮助癌症免疫逃逸，但它们在血液恶性肿瘤中的作用仍然存在争议，因此在试图推断实体瘤的有效治疗策略时应谨慎。我计划使用上述这些疾病的真实小鼠模型来确定Treg细胞在人类ABC-DLBCL和MM的起始和进展中的作用。我预计，在小鼠中产生的肿瘤与其人类对应物的种间比较癌基因组学将导致鉴定致病/驱动基因突变，其可以作为预后生物标志物和/或治疗靶点。另一方面，更好地了解Treg在血液恶性肿瘤背景下的功能将提供关于如何以及何时调节其活性以刺激免疫系统控制肿瘤生长的见解。

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.