C MYC EXPRESSION DURING ALV LYMPHOMAGENESIS

描述：(改编自调查人员摘要)禽白血病病毒 (ALV)在淋巴瘤易感性人群中快速诱导转移性法氏囊淋巴瘤 鸡株克隆扩增含前病毒c-myc的B细胞 转化的卵泡内的基因整合。脉冲追逐标记 增殖和法氏囊移行的测量将检查c-myc如何 过度表达会导致这些转化的卵泡迅速扩张。相同 分析将确定为什么从淋巴瘤转化的毛囊具有抗药性 鸡的菌株不会扩张并形成肿瘤。法氏囊移植 从逆转录病毒载体过度表达外源myc的祖细胞将测试 无论这种耐药性是由于ALF LTR驱动的myc表达减少所致，还是 改变靶细胞对myc表达的反应。肿瘤的免疫组织化学研究 在淋巴瘤易感的鸟类中，myc的作用很早就显示出血管生成。 C-myc或v-myc转化的卵泡和肿瘤的分期。血管生成 在B细胞中由myc过表达诱导的活性将用 血管内皮细胞增殖、迁移和血管的体外和体内检测 成长。血管生成将在法氏囊淋巴肿大过程中通过 表达myc和/或血管生成基因的法氏囊祖细胞的移植 来自逆转录病毒载体的抑制剂，以确定是否抑制 血管生成阻止myc转化的卵泡或其早期生长 形成转移性淋巴瘤的能力。法氏囊淋巴细胞过表达myc 显示血管内皮细胞生长因子(VEGF)产生增加。这个 这种内皮生长因子在myc诱导的血管生成中的作用 通过B细胞中血管内皮生长因子的高表达或低表达来评估。其影响 在低myc B细胞系中过表达的血管内皮生长因子的特征是 血管内皮细胞增殖、迁移和血管生成分析及法氏囊 过度表达血管内皮生长因子的祖细胞将被评估其诱导 体内血管生成。血管内皮生长因子基因将从myc过度表达的B中删除 通过同源重组，以确定这是否减少 体外血管生成活性和体内血管生成肿瘤的形成。这些 研究将深入了解myc和血管内皮生长因子诱导的血管生成的作用 在淋巴瘤的发生过程中。实验模型的发现将 应用于人类淋巴瘤和其他癌症的血管生成研究 涉及c-myc表达下调，以确定myc是否诱导 血管生成有助于myc过度表达与 人类癌症。

DESCRIPTION: (Adapted from the investigator's abstract) Avian leukosis virus (ALV) rapidly induces metastatic bursal lymphomas in lymphoma-susceptible chicken strains, after clonal expansion of B cells harboring a proviral c-myc gene integration within transformed follicles. Pulse-chase labelling measurements of proliferation and bursal emigration will examine how c-myc overexpression induces rapid expansion of these transformed follicles. The same analysis will determine why transformed follicles from lymphoma-resistant chicken strains fail to expand and form tumors. Transplantation of bursal progenitors overexpressing exogenous myc from retroviral vectors will test whether this resistance results from reduced ALF LTR-driven myc expression, or altered target cell response to myc expression. Immunohistochemical studies of the effects of myc in lymphoma-susceptible birds revealed angiogenesis at early stages within c-myc or v-myc-transformed follicles and tumors. The angiogenic activity induced by myc overexpression in B cells will be characterized using in vitro and in vivo assays of endothelial proliferation, migration, and vessel growth. Angiogenesis will be manipulated during bursal lymphomagenesis by transplantation of bursal progenitors expressing myc and/or angiogenic inhibitors from retroviral vectors, to determine whether inhibition of angiogenesis prevents early growth of myc-transformed follicles or their ability to form metastatic lymphomas. Bursal lymphocytes overexpressing myc show increased vascular endothelial growth factor (VEGF) production. The contribution of this endothelial growth factor to myc-induced angiogenesis will be assessed by overexpressing or underexpressing VEGF in B cells. The effects of VEGF overexpression in low myc B cell lines will be characterized by endothelial proliferation, migration, and angiogenesis assays, and bursal progenitors overexpressing VEGF will be assessed for their ability to induce angiogenesis in vivo. The VEGF gene will be deleted from myc-overexpressing B cell lines by homologous recombination, to determine whether this reduces angiogenic activity in vitro, and formation of angiogenic tumors in vivo. These studies will give insight to the role of myc- and VEGF-induced angiogenesis during the generation of lymphomas. Findings from the experimental model will be applied to studies of angiogenesis in human lymphomas and other cancers involving de-regulated c-myc expression, to determine whether myc-induced angiogenesis contributes to the common association of myc overexpression with human cancers.