EB病毒相关性T/NK淋巴瘤转基因小鼠系列模型的建立及疾病表型分析

Epstein-Barr virus–associated T/NK–cell lymphomas (EBV+ T/NK-NHL) are T-cell or natural killer (NK)-cell neoplasms that usually originate from the malignant transformation of T or NK cells with the persistence of latent EBV infection. They commonly express cytotoxic markers, such as TIA1, granzyme B, or perforin. These lymphomas account for approximately 40% of total T/NK-NHL disease entities and have a geographical predilection for Asia. For the time being, limited understanding of the heterogeneous T/NK-NHL has greatly hindered the clinical success and development of effective target therapies to cure the diseases. Therefore, there is an urgent need to develop more sophisticated animal models to closer resemble EBV+ T/NK-NHL in order to better understand the heterogeneous group of lymphomas. However, no such kind of animal model with high fidelity to human EBV+ T/NK-NHL is now available. Based on our previous data on aggressive NK cell leukemia (ANKL), our findings strongly suggest EBV-encoded small RNAs (EBERs), IL-10 and IL-18 might play critical roles in lymphomagenesis of EBV+ T/NK-NHL. In the present study, we propose to employ cytotoxic gene promoter-driven transgenic strategy of EBERs, IL-10 or IL-18 for establishing a series of transgenic mouse models for EBV+ T/NK-NHL. Through the access to early stages of mature T/NK-cell transformation and their multi-step oncogenesis, the model systems will ultimately update our current understanding of EBV+ T/NK-NHL, provide more sophisticated model platforms to better serve our patients afflicted by the diseases and facilitate Chinese scholars to reframe the academic leadership in this field.

EB病毒相关性T/NK淋巴瘤 (EBV+ T/NK-NHL) 是起源于EBV 感染的一类T/NK-NHL的总称，大部分肿瘤细胞表达细胞毒性相关蛋白，占T/NK-NHL亚型的40% 以上。因对其发病机制认知有限，阻碍了疗效的提高。为解决这一关键问题，建立理想的动物模型具有紧迫性。申请者前期对EBV+ T/NK-NHL亚型，侵袭性NK细胞白血病的研究结果提示EBV非编码小核酸RNA (EBERs)，IL-10和IL-18可能是EBV+ T/NK-NHL关键的发病因素。为此，申请者将分别以EBERs，IL-10和IL-18为目的基因，以细胞毒性相关基因启动子为表达启动子，构建EBV+ T/NK-NHL系列转基因小鼠模型。通过对EBV+ T/NK-NHL模型发病的全程动态研究，探讨关键的启动和驱动机制，达到加强源头创新的平台建设；为研发诊治策略提供理论基础；利于国内在该领域形成优势方向等三重目的。

EB病毒相关性T/NK淋巴瘤 （EBV+ T/NK-NHL）是起源于EBV感染的一类T/NK-NHL的总称，占T/NK-NHL亚型的40%以上。前期对EBV+T/NK-NHL亚型，侵袭性NK细胞白血病的研究结果提示EBV非编码小核酸RNA （EBERs），IL-10和IL-18可能是EBV+T/NK-NHL关键的发病因素。为此，分别以EBERs，IL-10和IL-18为目的基因，构建了转基因小鼠模型。其中，EBER1，EBER2全血或者NK细胞特异性过表达小鼠诱导一年以上未见发病。IL-10，IL-18全血双过表达转基因小鼠表现出HLH临床表现，符合继发性HLH诊断标准，可以作为良好的HLH模型用于疾病发病的全程动态研究，探讨关键的启动和驱动机制。目前体内体外实验均证明高剂量IL-10和IL-18可以异常激活巨噬细胞，不同于经典巨噬细胞激活表型M1或者M2型。另外，IL-10，IL-18双过表达转基因小鼠骨髓造血干细胞向粒单核细胞祖细胞分化。深层的分子机制目前正处于假说验证阶段。该研究将为HLH研发诊治策略提供创新性理论基础，利于国内在该领域形成优势方向。