Targeting of EBV Latency in Burkitt's Lymphoma

伯基特淋巴瘤（Burkitt lymphoma，BL）是发展中国家最常见的小儿淋巴组织增生性疾病，与EB病毒（Epstein巴尔病毒，EBV）密切相关。这些恶性肿瘤可以用化疗治愈，但复发或耐药的疾病是很常见的，通常是致命的。我们假设，EB病毒在地方性BL中的存在既可用于监测对治疗的反应，也可作为治疗靶点。在我们的第一个目标，我们建议研究EB病毒病毒载量的BL患者登记的治疗方案。我们将确定EBV病毒载量是否与治疗反应相关，或相反与复发或耐药疾病相关。我们还将研究化疗对病毒再激活的影响。 我们进一步假设抗病毒药物叠氮胸苷（AZT）通过一种独特的靶向机制诱导EBV+ BL细胞凋亡：抑制NF-κ B和破坏病毒潜伏期。这导致AZT被病毒激酶磷酸化和细胞凋亡。 因此，AZT本质上是一种利用EBV存在的廉价基因治疗形式。 对于复发的地方性BL没有有效的治疗方法。在目标2中，我们将对这些患者进行化疗/抗病毒（AZT，Hydrea）治疗试验。已知常用的化疗剂诱导EBV裂解周期，包括病毒胸苷激酶，从而增强AZT的磷酸化。我们的团队由儿科和成人血液学家、病毒学家、研究护士和病理学家组成，提供了这项转化研究所需的多学科专业知识。我们的合作者位于病毒性淋巴组织增生性疾病常被诊断的独特地点，具有良好的基础设施参与这项研究。通过该项目获得的数据应广泛适用于发生在免疫受损个体中的高级别淋巴瘤。这些研究应该导致新的，非致癌的，简化的治疗方法，适用于发展中国家的这种常见肿瘤。

Burkitt lymphoma (BL), the most common pediatric lymphoproliferative disease in developing nations, is highly associated with Epstein Barr virus (EBV). These virulent tumors can be cured with chemotherapy but relapsed or resistant disease is quite common and generally fatal. We hypothesize that the presence of EBV in the endemic form of BL can be used both to monitor response to therapy and as a therapeutic target. In our first aim we propose to study EBV viral load in BL patients enrolled on a therapeutic protocol. We will determine whether EBV viral load correlates with response to therapy or conversely with relapsing or resistant disease. We will also investigate the effect of chemotherapy on viral reactivation. We further hypothesize that the antiviral agent azidothymidine (AZT) induces apoptosis in EBV+ BL through a unique, targeted mechanism: suppression of NF-kappaB and disruption of viral latency. This results in phosphorylation of AZT by viral kinases and apoptosis. Therefore, AZT is essentially an inexpensive form of gene therapy that exploits the presence of EBV. There is no effective therapy for relapsed endemic type BLs. In aim 2 we will conduct a trial of chemo/antiviral (AZT, hydrea) therapy for these patients. Commonly available chemotherapeutic agents are known to induce the EBV lytic cycle including viral thymidine kinase and thereby potentiate phosphorylation of AZT. Our group, comprised of pediatric and adult hematologists, virologists, research nurses and pathologists offers multidisciplinary expertise required for this translational study. Our collaborators, located at a unique site where viral lymphoproliferative diseases are commonly diagnosed, have excellent infrastructure in place to participate in this study. Data acquired through this project should be broadly applicable to high grade lymphomas that occur in Immune compromised individuals. These studies should lead to new, non-carcinogenic, abbreviated therapy that is applicable in developing nations for this common tumor.