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通过病毒转导激活， Abelson鼠白血病病毒GAG-ABL融合体和在人白血病中与 费城染色体易位，包括慢性粒细胞性 白血病和急性淋巴细胞白血病，它们产生BCR-ABL融合。 本提案的总体目标是了解ABL在以下方面的作用： 造血干细胞的生长调节及其发病机制 白血病 我们将在成功发展的基础上， 造血组织培养和白血病发生的体内模型， 帮助确定了ABL基因的靶细胞。 进一步 结构变化和功能后果的定义 ABL酪氨酸激酶活性的激活，以及它们与 细胞信号传导途径，将进行。 BCR的作用 转录、翻译和翻译后控制基因 ABL基因在人类白血病中的表达和功能将是 研究了 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 人慢性粒细胞白血病向急变的进展 相位 中国人Ph阳性白血病病理生物学的继续研究 人类宿主及其对治疗的反应。 我们将 修改现有的聚合酶链反应技术， 残余肿瘤负荷的定量评价及其临床意义 影响，特别是在骨髓移植后。 的 慢性粒细胞白血病人群的生长特征 在疾病进展的不同阶段， 在SCID小鼠模型中评估。 造血系统与 元素和骨髓衍生的基质元素将在一个 这种方式概括了骨髓的结构。 我们希望能够 在这种特殊的环境中有效地培养白血病的干细胞 环境，并可能了解更多关于正常和 异常的干细胞生长调节

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.