THE MURINE ALL-1 GENE--TUMORIGENESIS AND DEVELOPMENT

活动性白血病是人类毁灭性疾病的一种形式。 从这些白血病中发现的染色体重排导致了 细胞异常相关基因的鉴定 扩散。发现一系列易位断点和缺失 人类急性白血病的一个子集的改变具有类似的特征 在人类染色体11q23上有断裂的一端。这一地区有 最近克隆了一个大基因(ALL-1)，该基因与 果蝇三胸基因已被鉴定。ALL-1基因已经被 在这些人类中被发现与大量不同的基因融合 白血病。本提案的重点是识别和操纵 小鼠同源的人类ALL-1基因，以研究其在 哺乳动物的正常发育。鼠标提供了一种极好的 研究哺乳动物ALL-1的实验系统，因为它是 也有可能直接操纵老鼠的遗传内容 至于研究发展的各个阶段。此外，携带病毒的老鼠 基因改变--胚胎干细胞同源重组的结果 细胞，是确定体内正常的终极模型系统 细胞原癌基因的作用。这项提案计划完成 小鼠ALL-1基因和All-1同源基因的克隆及序列分析 识别和表征可选的拼接形式，提供 了解ALL-1在人类白血病中的作用的重要基础。 此外，研究将集中在阐明表达模式 目的是了解这种基因如何在发育过程中 基因是受调控的。最后，我们将识别并产生突变小鼠 缺乏ALL-1的表达以了解其在发育中的作用。这些 突变的小鼠将为未来的目标识别 ALL-1的功能成分以及识别受 全部为1。它是通过对作用机制和 ALL-1基因的调控是未来治疗研究的重点 这些人类急性白血病将基于。

Active leukemias are one form of devastating illness in humans. Chromosomal rearrangements identified from these leukemias has led to the identification of the genes responsible for abnormal cellular proliferation. A series of translocation breakpoints and deletions found altered in a subset of human acute leukemias have the similar feature of having one end of the break on human chromosome 11q23. This region has recently been cloned and a large gene (ALL-1) with homology to the Drosophila trithorax gene has been identified. The ALL-1 gene has been found to be fused to a large number of different genes in these human leukemias. This proposal focuses on identifying and manipulating the mouse homolog of the human ALL-1 gene in order to study its role in normal mammalian development. The mouse provides an excellent experimental system for the study of ALL-1 in mammals, since it is possible to directly manipulate the genetic content of the mouse as well as to study all stages of development. In addition, mice that carry altered genes, the result of homologous recombination in embryonic stem cells, are the ultimate model system for determining the normal in vivo role of cellular protooncogenes. This proposal plans to complete the cloning and sequencing of the mouse homolog of the ALL-1 gene and identify and characterize alternatively spliced forms, providing an important basis for understanding the role of ALL-1 in human leukemias. In addition, research will focus on elucidating the pattern of expression of this gene during development with the goal of understanding how this gene is regulated. Finally, we will identify and generate mutant mice lacking All-1 expression to understand its role in development. These mutant mice will provide a foundation for future goals of identifying the functional components of All-1 as well as identifying genes regulated by All-1. It is through an understanding of the mechanisms of action and regulation of the All-1 gene that future research focusing on treatment of these human acute leukemias will be based.