STUDIES OF BCR/ABL LEUKEMOGENESIS IN MICE

描述：（改编自研究者摘要）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细胞急性淋巴细胞白血病是最常见的 血液恶性肿瘤，目前对这些疾病的治疗是 不足表达t（9;22）Ph染色体的产物，BCR！ABL 融合基因，在造血系统中通过转基因小鼠的产生 小鼠或通过逆转录病毒转导和骨髓移植， 证实BCR/ABL是白血病特异性癌基因， 的CML。本申请的长期目标是一个更完整的 对人类ph阳性病理生理学的分子和遗传学了解 白血病，特别是骨髓增生性疾病CML。这些目标将是 通过使用逆转录病毒骨髓感染/移植完成 小鼠模型系统，其准确和定量地模拟人类CML和 Ph阳性B淋巴细胞白血病，并将有两个具体目标。上 目的：探讨BCR/ABL致白血病的重要信号通路 通过检测BCR/ABL突变体，通过进一步分析 为了通过Bcr/Abl融合蛋白直接结合Grb 2衔接蛋白， 以及通过使用在信号分子中具有种系突变的小鼠。在 第二个目标，启动CML样疾病的骨髓靶细胞 BCR/ABL诱导的B淋巴细胞白血病将被表征和分离 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， 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CML细胞中。这些知识对于提高 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.