PATHOGENETIC MECHANISMS IN FELINE LEUKEMIA

该计划的长期目标是确定多个事件 家猫淋巴恶性肿瘤发病机制中的相互作用。 该近交物种的白血病-淋巴瘤发病率是所有物种中最高的 动物和自然发生的猫白血病的水平感染 病毒与其对白血病发生的易感性增加有关。 活动 在长时间的病毒血症期间发生的病毒大多是未知的，除了 受感染的猫会出现免疫抑制，并且在许多胸腺中 淋巴瘤 c-myc 原癌基因是转导的或插入的 激活。 虽然该疾病的近端白细胞生成物尚不清楚， 有证据表明病毒和内源性之间存在同源重组 细胞逆转录病毒元件。 这些内源性的特征 家猫基因组序列和两种常见的分离 猫科动物 c-myc 基因的等位基因的出现为 目前的研究。 有证据表明 c 处的一种纯合性 myc 位点很少见，而另一种类型的纯合性则常见 发生在猫身上的疾病可能与淋巴瘤发病率增加有关。 具体目的如下：（1）考察特定病毒的作用 内源性和外源性逆转录病毒之间的亚群和重组 决定体内组织趋向性和疾病特异性的基因； (2) 检查变异体对宿主免疫反应的损害 确定免疫抑制的病毒决定因素； (3)确定 分离的 c-myc 等位基因在功能和功能方面的遗传特性 结构差异并确认观察结果普遍延伸 检测猫基因组 DNA 中类似的结构变化；和（4） 识别参与重排的近端代理 c-myc 基因并确定是否存在激活的等位基因特异性 随之而来的生物活性。 该模型系统提供了以下机会： 检查外源和内源逆转录病毒基因之间的相互作用 以及原病毒元件和广泛涉及的原癌基因之间 淋巴发育中具有生物学意义的等位基因变异 远交动物物种中的肿瘤。

The long-term goal of this program is to identify the multiple events that interplay in the pathogenesis of lymphoid malignancies in the domestic cat. This outbred species has the highest incidence of leukemia-lymphoma of any animal, and horizontal infection by the naturally occurring feline leukemia virus is related to its increased susceptibility to leukemogenesis. Events that occur during the prolonged viremic period are mostly unknown, except that infected cats become immunosuppressed and that in many thymic lymphomas the c-myc proto-oncogene is either transduced or insertionally activated. While the proximal leukomogens for the disease are unknown, there is evidence for homologous recombination between viral and endogenous cellular retrovirus elements. The characterization of these endogenous sequences of the domestic cat genome and isolation of two commonly occurring alleles of the feline c-myc gene provide the basis for the present study. There is evidence that one type of homozygosity at the c- myc locus is rare, while the other type of homozygosity that commonly occurs in cats may be associated with increased frequency of lymphomas. The specific aims are as follows: (1) examine the role of specific viral subgroups and recombination between endogenous and exogenous retroviral genes in dictating in vivo tissue tropism and disease specificities; (2) examine the impairment of the host's immune response by the variants to identify the viral determinants for immunosuppression; (3) determine genetic properties of the isolated c-myc alleles in terms of functional and structural differences and confirm that the observations extend generally to the detection of similar structural changes in cat genomic DNAs; and (4) identify the proximal agents that are involved in the rearrangement of the c-myc gene and determine if there is allele specificity for activation and consequent biological activity. The model system offers the opportunity of examining the interaction between exogenous and endogenous retrovirus genes and between provirus elements and a widely implicated proto-oncogene with biologically significant allelic variations in the development of lymphoid tumors in an outbred animal species.