GCKR MEDIATED SIGNAL TRANSDUCTION AND LEUKEMIC TRANSFORM

描述(申请人的描述)： 慢性粒细胞白血病(CML)是一种克隆性骨髓增生性疾病 原始的造血干细胞。慢性粒细胞白血病约占 占所有成人白血病的25%。Bcr-abl癌基因可能代表 几乎在所有CML中都有启动事件，尽管其他遗传事件是 完全恶性表型所必需的。最近描述的 已知丝氨酸苏氨酸激酶GCK和GCKR激活途径 被认为介导了bcr-abl的转化能力。具体来说， 根据将在初步研究项下提交的工作， 申请者假设GCKR与GCKR明确关联，并且是 由BCR-ABL激活，可能是BCR-ABL的关键元素 转变潜力。在此基础上，他们建议：1)检查 调解GCKR之间关联的基本要素和要求 和BCR-ABL；2)检查BCR-ABL的功能后果 与GCKR的关系；3)评估GCK的体内转化能力 和GCKR。GCKR在BCR-ABL介导的转化中的作用 将有助于更好地理解致癌机制。 转变，从而允许发展改进的治疗和 慢性粒细胞白血病的预测策略。申请者在分子方面的培训 生物学、免疫学和临床肿瘤学，除了他的直接 最初克隆GCKR的经验使他处于独特的地位 继续进行这里提出的研究。

DESCRIPTION (Applicant's Description): Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder of the primitive hematopoietic stem cell. CML accounts for approximately 25% of all adult leukemia. The BCR-ABL oncogene probably represents the initiating event in nearly all CML, although additional genetic events are required for the full malignant phenotype. The recently described serine-threonine kinases GCK and GCKR are known to activate the pathway that is thought to mediate the transforming ability of BCR-ABL. Specifically, based on work that is to be presented under Preliminary Studies, the applicants hypothesize that GCKR specifically associates with, and is activated by, BCR-ABL and is likely a critical element in BCR-ABL's transforming potential. Based on this they propose to: 1) examine the basic elements and requirements that mediate the association between GCKR and BCR-ABL; 2) examine the functional consequences of the BCR-ABL relationship with GCKR; 3) assess the in vivo transforming potential of GCK and GCKR. Elucidating the role of GCKR in BCR-ABL mediated transformation will allow for a better understanding of the mechanism of oncogenic transformation, and thus allow for the development of improved treatment and prognostication strategies for CML. The applicant's training in molecular biology, immunology, and clinical oncology, in addition to his direct experience with the initial cloning of GCKR put him in the unique position to pursue the studies proposed here.