PATHOGENETIC MECHANISMS IN FELINE LEUKEMIA

该计划的长期目标是确定符合以下条件的多个事件 家猫淋巴系恶性肿瘤发病机制的相互作用。 这种近亲繁殖的物种是白血病淋巴瘤发病率最高的物种 动物，以及自然发生的猫白血病的水平感染 病毒与其对白血病的易感性增加有关。事件 在延长的病毒期发生的病毒大多是未知的，除了 受感染的猫会受到免疫抑制，在许多胸腺中 淋巴瘤原癌基因c-myc被转导或插入 激活了。虽然这种疾病的近端白血球致病因素尚不清楚， 有证据表明病毒和内源病毒之间存在同源重组 细胞逆转录病毒成分。这些内生性的特征 家猫基因组序列测定及两株常见家猫的分离 猫c-myc基因的发生等位基因为 目前的研究。有证据表明，c-基因的一种纯合性- MYC基因座很少见，而另一种类型的纯合性通常 发生在猫身上可能与淋巴瘤的发生频率增加有关。 具体目标如下：(1)研究特定病毒的作用 内源性和外源性逆转录病毒亚群及其重组 决定体内组织嗜性和疾病特异性的基因； 检测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等位基因的功能和遗传特性 结构差异，并确认观察结果大体上是 用于检测猫基因组DNA中类似的结构变化；以及(4) 找出参与基因重排的近端分子 C-myc基因，并确定是否存在等位基因特异性激活和 随之而来的生物活动。模型系统提供了一个机会 检测外源性和内源性逆转录病毒基因之间的相互作用 在前病毒成分和广泛牵连的原癌基因之间 淋巴样细胞发育过程中显著的生物等位基因变异 远亲繁殖的动物物种中的肿瘤。

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.