Targeting of EBV Latency in Burkitt's Lymphoma

伯基特淋巴瘤（BL）是发展中国家最常见的儿童淋巴细胞增生性疾病，与eb病毒（EBV）高度相关。这些恶性肿瘤可以通过化疗治愈，但复发或耐药的疾病很常见，通常是致命的。我们假设EBV在地方性BL中的存在既可以用来监测治疗反应，也可以作为治疗靶点。在我们的第一个目标中，我们建议研究接受治疗方案的BL患者的EBV病毒载量。我们将确定EBV病毒载量是否与治疗反应相关，或与复发或耐药疾病相反。我们还将研究化疗对病毒再激活的影响。

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.