Investigating the origins and pathogenesis of anaplastic large cell lymphoma

间变性大细胞淋巴瘤（ALCL）是一种侵袭性外周T细胞非霍奇金淋巴瘤，通常以表达CD 30和缺乏功能性T细胞受体（TCR）为特征。ALCL可分为四种亚型，包括系统性/淋巴结间变性淋巴瘤激酶（ALK）+和ALK-ALCL、皮肤ALCL和乳房植入体相关ALCL（BIA-ALCL）。由于相互矛盾的证据，ALCL的起源和发病机制在很大程度上是未知的。Turner实验室先前的工作表明ALK+ ALCL的胸腺起源，外周的继发性事件触发完全恶性肿瘤。进一步的研究表明，这种继发性事件可能涉及某种抗原刺激，导致TCR下调并使ALCL进展。有趣的是，BIA-ALCL也被认为是由存在于毛面乳房植入体表面的慢性抗原刺激引起的。在这个项目中，我们建议研究ALCL发展的原因和方式，特别关注阐明抗原刺激的性质，以及这如何与功能性TCR的丧失和ALCL的后续发展相关。希望这项工作将有助于合理设计新的和/或改进的ALCL治疗策略。

Anaplastic large cell lymphoma (ALCL) is an aggressive form of peripheral T cell non-Hodgkin lymphoma, often characterised by the expression of CD30 and the absence of a functional T cell receptor (TCR). ALCL can be divided into four subtypes, including systemic/nodal anaplastic lymphoma kinase (ALK)+ and ALK- ALCL, cutaneous ALCL and breast implant associated ALCL (BIA-ALCL). Due to conflicting evidence, the origin and pathogenesis of ALCL is largely unknown. Previous work by the Turner lab has suggested a thymic origin for ALK+ ALCL, with secondary events in the periphery triggering full blown malignancy. Further work suggested that this secondary event could involve some sort of antigenic stimulus which leads to the downregulation of the TCR and enables ALCL progression. Interestingly, BIA-ALCL is also thought to be caused by a chronic antigenic stimulus, present on the surface of textured breast implants. In this project, we propose to investigate why and how ALCL develops, with specific focus on elucidating the nature of the antigenic stimulus and how this may be linked to the loss of a functional TCR and the subsequent development of ALCL. It is hoped that this work will facilitate the rational design of new and/or improved therapeutic strategies for ALCL.