PROGRESSION OF CHRONIC MYELOGENOUS LEUKEMIA

描述(申请者的描述)：职业发展奖将 提供获得深入培训和经验的机会 癌症和血液学研究要点。拟议的培训包括 授课学习、专业会议以及与 癌症和白血病研究领域。研究计划的目标是 提供一个学习癌症和癌症研究基本技术的机会 恶性血液病，学会创造性思维和分析性思维， 并培养必要的技能，以培养成功的独立 研究计划。 罗伯特·A·温伯格博士作为主要赞助商和乔治博士的组合 问：戴利作为联合赞助商将提供出色的指导。温伯格博士已经 培训优秀调查员的既定记录。戴利医生有一个 在人类白血病研究和临床研究方面有很强的背景 血液学家他为内科医生和科学家树立了很好的榜样。这个 怀特黑德研究所的教育机会和资源 生物医学研究提供的是优秀的，并将补充强大 温伯格博士和戴利博士的指导。 这项拟议的研究试图解释慢性阻塞性肺疾病的临床过程。 髓系白血病(CML)。CML最初表现为临床上的 可控的慢性期疾病，特征是过度增殖 相对正常的细胞。CML不可避免地发展到BLAST阶段，一个虚拟的 治疗可治愈的急性白血病。基因的变化导致了 爆炸的进展尚不清楚。 温伯格实验室最近开发了一种合作模式 人类细胞中的致癌基因，表明人类原代细胞可以 由病毒癌基因、ras癌基因和 L的聚合酶基因。这个实验系统产生了一个人体模型 致癌作用可以用来制定一些特异的、可检测的 可能解释慢性期CML向急变期进展的假说 相位。基于对人类慢性期和急变期的观察 NOD/SCID免疫缺陷小鼠细胞植入方式不同的假说 关于慢性期的进展，CML可以在体内进行测试。 这项研究的前两个部分阐述了端粒酶在 慢性粒细胞白血病的自然历史。后两部分探讨癌基因在肿瘤细胞中的作用。 急变期慢性粒细胞白血病的发病机制及建立多步模型的尝试 解释慢性期CML向急变期的进展。

DESCRIPTION (Applicant's Description): A career development award will provide the opportunity to obtain in depth training and experience in the essentials of cancer and hematology research. The proposed training involves didactic study, professional meetings, and collaborations with leaders in the fields of cancer and leukemia research. The goal of the research plan is to provide an opportunity to learn basic techniques in the study of cancer and malignant hematologic diseases, to learn to think creatively and analytically, and to develop the skills necessary to develop a successful independent research program. The combination of Dr. Robert A. Weinberg as a primary sponsor and Dr. George Q. Daley as a co-sponsor will provide outstanding mentorship. Dr. Weinberg has an established record of training outstanding investigators. Dr. Daley has a strong background in the study of human leukemias and as a clinical hematologist he provides an excellent role model of a physician-scientist. The educational opportunities and the resources that the Whitehead Institute for Biomedical Research provides are outstanding, and will complement the strong mentorship of Dr. Weinberg and Dr. Daley. The proposed research seeks to explain the clinical course of chronic myelogenous leukemia (CML). CML initially manifests as a clinically manageable chronic phase disease, characterized by a hyperproliferation of relatively normal cells. CML inevitably progresses to blast phase, a virtually u n t reatable acute leukemia. The genetic changes responsible for the progression to blast are unknown. The Weinberg laboratory has recently developed a model for cooperating oncogenes in human cells, demonstrating that primary human cells can be transformed by the combination of a viral oncogene, a ras oncogene, and the t e l o merase gene. This experimental system yields a model of human carcinogenesis that can be used to formulate a number of specific, testable hypotheses that may explain the progression of chronic phase CML to blast phase. Building on the observation that human chronic phase and blast phase cells engraft differently in the immunocompromised NOD/SCID mouse, hypotheses regarding the progression of chronic phase CML can be tested in vivo. The first two parts of the research address the role of telomerase in the natural history of CML. The second two parts explore the role of oncogenes in the pathogenesis of blast phase CML and attempt to build a multi-step model to explain the progression of chronic phase CML to blast phase.