C MYC EXPRESSION DURING ALV LYMPHOMAGENESIS

ALV 淋巴细胞生成期间的 C MYC 表达

• 批准号: 6946179
• 负责人: M ALANNA RUDDELL
• 金额: $ 6.5万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946179
• 关键词: B cell lymphoma; B lymphocyte; angiogenesis; apoptosis; avian leukosis virus; bursa of Fabricius; cell migration; cell proliferation; chickens; gene expression; immunocytochemistry; in situ hybridization; neoplasm /cancer genetics; polymerase chain reaction; protooncogene; vascular endothelial growth factors; viral carcinogenesis

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.

描述：（改编自研究者摘要）禽白血病病毒 (ALV)快速诱导淋巴瘤易感的转移性囊淋巴瘤 鸡株，克隆扩增携带前病毒c-myc的B细胞后 转化卵泡内的基因整合。脉冲追踪标记 测量增殖和囊移行将检查c-myc 过表达诱导这些转化的卵泡快速扩增。相同的 分析将确定为什么从淋巴瘤抗性转化的卵泡 鸡品系不能扩张并形成肿瘤。法氏囊移植术 从逆转录病毒载体过表达外源myc的祖细胞将测试 这种耐药性是否由ALF LTR驱动的myc表达减少引起，或 改变靶细胞对myc表达的反应。的免疫组化研究 myc在淋巴瘤易感鸟类中的作用显示， c-myc或v-myc转化的卵泡和肿瘤内的阶段。血管生成 由myc在B细胞中过表达诱导的活性将使用 内皮细胞增殖、迁移和血管生成的体外和体内测定 增长在法氏囊淋巴瘤形成过程中， 表达myc和/或血管生成的囊祖细胞的移植 来自逆转录病毒载体的抑制剂，以确定是否抑制 血管生成阻止了myc转化的卵泡或其 形成转移性淋巴瘤的能力。过表达myc的法氏囊淋巴细胞 显示血管内皮生长因子（VEGF）产生增加。的 这种内皮生长因子对myc诱导的血管生成的贡献将 通过B细胞中VEGF的过表达或低表达来评估。的影响 在低myc B细胞系中VEGF过表达的特征在于： 内皮细胞增殖、迁移和血管生成测定，以及法氏囊 将评估过表达VEGF的祖细胞诱导细胞凋亡的能力。 体内血管生成。将VEGF基因从myc过表达的B中删除 细胞系通过同源重组，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 这些研究将使人们了解myc和VEGF诱导的血管生成的作用 在淋巴瘤的产生过程中。实验模型的结果将 应用于人类淋巴瘤和其他癌症中血管生成的研究 涉及c-myc表达失调，以确定myc诱导的 血管生成有助于myc过度表达与 人类癌症