ROLE OF THE ABL ONCOGENE IN MURINE AND HUMAN LEUKEMIAS

ABL癌基因的酪氨酸激酶活性是一种生长刺激 造血细胞。ABL是通过病毒转导激活的 Abelson小鼠白血病病毒Gag-ABL融合和人类白血病 费城的染色体易位，包括慢性骨髓性 白血病和急性淋巴细胞白血病，它们会产生bcr-abl融合。 本提案的总体目标是了解ABL在 造血干细胞的生长调控及其在发病机制中的作用 白血病的症状。我们将在我们成功开发的基础上扩展 造血组织培养和体内白血病发生模型 帮助确定了ABL基因的靶细胞。进一步 《公约》的结构变化和职能后果的定义 ABL酪氨酸激酶活性的激活及其与 蜂窝信号通路，将被执行。《公约》的作用 转录、翻译和翻译后控制中的基因 ABL基因在人类白血病中的表达和功能的研究 学习。ABL与其他癌基因和生长因子的相互作用 系统将在培养和动物模型中进行评估，以了解 人类慢性粒细胞白血病发展到急变期 相位。我国Ph阳性白血病的病理生物学研究进展 人类宿主和他们对治疗的反应将会完成。我们会 修改当前的聚合酶链式反应技术，以允许更多 肿瘤残存负荷的定量评估及其临床意义 影响，特别是在骨髓移植后的环境中。这个 人慢性髓系白血病群体的生长特征 处于疾病进展不同阶段的白血病细胞 在SCID小鼠模型中进行评估。造血细胞之间的相互作用 元素和骨髓来源的基质元素将在 一种概括骨髓结构的方式。我们希望能够 为了在这个特殊的环境中有效地培养这种白血病的干细胞 环境，并有可能学到更多关于正常和 干细胞生长调节异常。

The tyrosine kinase activity of the ABL oncogene is a growth stimulus for hematopoietic cells. ABL is activated by viral transduction in the Abelson murine leukemia virus GAG-ABL fusion and in human leukemias with the Philadelphia chromosome translocation, including chronic myelogenous leukemia and acute lymphocytic leukemia, which generate BCR-ABL fusions. The overall goal of this proposal is to understand the roles of ABL in the growth regulation of hematopoietic stem cells and in the pathogenesis of leukemia. We will expand upon our successful development of hematopoietic tissue culture and in vivo models for leukemogenesis which have helped to define the target cells for the ABL gene. Further definition of the structural changes and functional consequences of the activation of the ABL tyrosine kinase activity, and their relation to cellular signalling pathways, will be carried out. The role of the BCR gene in the transcriptional, translational, and posttranslational control of expression and function of the ABL gene in human leukemias will be studied. Interactions of ABL with other oncogenes and growth factor systems will be evaluated in culture and animal models to understand the progression of human chronic myelogenous leukemia to the blast crisis phase. Continued studies on the pathobiology of Ph positive leukemias in the human host and their response to treatment will be done. We will modify current polymerase chain reaction technologies to allow more quantitative evaluation of residual tumor burden and its clinical implications, especially in the post-bone-marrow-transplant setting. The growth characteristics of populations of human chronic myelogenous leukemia cells at different stages of disease progression will be evaluated in the SCID mouse model. Interactions between hematopoietic elements and bone marrow derived stromal elements will be tested in a manner that recapitulates the architecture of marrow. We hope to be able to effectively grow the stem cells of this leukemia in this special environment, and potentially learn much about the nature of normal and abnormal stem cell growth regulation.