STUDIES OF BCR/ABL LEUKEMOGENESIS IN MICE

描述：(改编自调查人员的摘要)人类费城 (Ph)染色体阳性白血病，包括慢性粒细胞白血病(CML) 和B细胞急性淋巴细胞性白血病，是最常见的 恶性血液病，目前治疗这些疾病的方法是 不够充分。T(9；22)Ph染色体产物bcr！abl的表达 通过产生转基因小鼠的造血系统中的融合基因 小鼠或通过逆转录病毒转导和移植骨髓 证实bcr/abl是白血病特异的癌基因及其直接原因 CML的。这个应用程序的长期目标是一个更完整的 人类Ph阳性病理生理学的分子遗传学研究 白血病，特别是骨髓增生性疾病慢性粒细胞白血病。这些目标将是 通过使用逆转录病毒骨髓感染/移植实现的 一种准确定量模拟人类慢性粒细胞白血病和慢性粒细胞白血病的小鼠模型系统 PH值阳性的B淋巴细胞性白血病，并将有两个特定的目标。在第一个 目的：bcr/abl在白血病发生中起重要作用的信号通路将是 通过测试bcr/abl突变体，通过进一步的需求分析进行鉴定 为了通过BCR/Ab1融合蛋白直接结合Grb2接头蛋白， 并通过使用信号分子发生生殖系突变的小鼠。在……里面 第二个目标是启动CML样病的骨髓靶细胞 和BCR/ABL诱导的B淋巴细胞性白血病将被鉴定和分离 通过物理和免疫学方法。这些调查将增加重要的 对我们了解这些白血病的新信息，那就是 即使不是不可能，也很难从体外培养细胞的研究中获得， 或在原代人类慢性粒细胞白血病细胞中。这些知识将对改进 Ph阳性白血病的诊断和治疗

DESCRIPTION: (Adapted from the investigator's abstract) The human Philadelphia (Ph) chromosome-positive leukemias, including chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia, are among the most common hematological malignancies, and current therapy for these diseases is inadequate. Expression of the product of the t(9;22) Ph chromosome, the BCR!ABL fusion gene, in the hematopoietic system of mice by generation of transgenic mice or through retroviral transduction and transplantation of bone marrow has demonstrated that BCR/ABL is a leukemia specific oncogene and the direct cause of CML. The long term objective of this application is a more complete molecular and genetic understanding of the pathophysiology of human Ph-positive leukemias, particularly the myeloproliferative disease CML. These goals will be accomplished by the use of a retroviral bone marrow infection/transplantation mouse model system that accurately and quantitatively models both human CML and Ph-positive B-lymphoid leukemia, and will have two Specific Aims. In the first Aim, the signaling pathways important for leukemogenesis by BCR/ABL will be identified by testing BCR/ABL mutants, by further analysis of the requirement for direct binding of the Grb2 adapter protein by the Bcr/Abl fusion protein, and through the use of mice with germline mutations in signaling molecules. In the second Aim, the bone marrow target cells that initiate the CML-like disease and B-lymphoid leukemia induced by BCR/ABL will be characterized and isolated by physical and immunological methods. These investigations will add important new information to our understanding of these leukemias, that would be difficult if not impossible to obtain from studies in vitro, in cultured cells, or in primary human CML cells. This knowledge will be valuable for improving the diagnosis and treatment of the Ph-positive leukemias.