MDS EVOLUTION TO AML--MOLECULAR BIOLOGY AND CYTOKINES

MDS 向 AML 的演变——分子生物学和细胞因子

• 批准号: 6269877
• 负责人: HARVEY D PREISLER
• 金额: $ 23.81万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-31 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6269877
• 关键词: acute lymphocytic leukemia; acute myelogenous leukemia; carcinogenesis; clinical research; cytokine; hematopoiesis; human subject; neoplasm /cancer genetics; neoplasm /cancer remission /regression; neoplastic growth; preneoplastic state; prognosis

Project III is devoted to the study of poor prognosis AML and its evolution from a myelodysplastic state. The common molecular genetic abnormalities present in MDS and AML will be identified and compared so that combinations of abnormalities present in AML but not in MDS can be identified. These comparisons will utilize two strategies: a comparison of groups of patients and the serial study of individual patients from the time at which MDS is diagnosed through the time that AML has appeared. The goals of these studies are threefold: 1: to develop and identify the combinations of genetic lesions which are associated with the development of AML 2- to identify the biologic effects of these lesions on hemopoietic cells; and 3-to relate the clinical characteristics of the diseases and their response to treatment to the genetic lesions and their biological consequences. Specific in vitro studies designed to directly test the observed relationship between the various observed phenomena will be performed as well. At the clinical level we are particularly interested in the phenomenon of regrowth resistance as a cause of remission induction failure and also in the association of a return of myelodysplastic hemopoiesis after therapy [instead of either leukemia or normal cells] with short leukemia-free remissions. We hypothesize that aberrant cytokine production by leukemia cells and together with abnormal responses to cytokine production, both as a consequence of the genetic lesions which are present in AML and in MDS, play a major role in both regrowth resistance of AML and also in the early recurrence of leukemia in patients who achieve 'myelodysplastic' remission after treatment for AML. We will document the involvement of specific genetic abnormalities in both processes and will develop strategies for suppressing abnormal cytokine production and/or the abnormal responses AML cells to cytokines. These strategies will be tested in patients and the successful ones will be prospectively tested in pilot clinical trials. The studies proposed here hold out the promise of the development of an understanding of the impact of genetic anbormalitites on the cell and clinical biology of AML and also the promise of facilitating the development of the means to suppress the biologic consequences of these abnormalities so as to improve treatment outcome.

项目III致力于不良预后AML及其相关研究 从骨髓增生异常状态进化而来。 常见分子 MDS 和 AML 中存在的遗传异常将被识别并 进行比较，发现 AML 中存在异常组合，但 不在MDS中可以被识别。 这些比较将利用两个 策略：患者组的比较和系列研究 个别患者从MDS被诊断之时起 AML出现的时间。 这些研究的目标是 三重：1：开发和识别遗传组合 与 AML 2- 发展相关的病变 确定这些病变对造血细胞的生物学影响；和 3-联系疾病的临床特征及其反应 遗传病变的治疗及其生物学后果。 旨在直接测试观察到的特定体外研究 各种观察到的现象之间的关系将是 也执行了。 在临床层面我们特别感兴趣 作为缓解原因的再生抵抗现象 感应失败以及返回的关联 治疗后骨髓增生异常造血[而不是白血病 或正常细胞]具有短暂的无白血病缓解。 我们假设 白血病细胞异常产生细胞因子并与 对细胞因子产生的异常反应，都是由于 AML 和 MDS 中存在的遗传病变，发挥着重要作用 在 AML 的再生抵抗以及早期 达到“骨髓增生异常”的患者白血病复发 AML 治疗后缓解。 我们将记录 在这两个过程中都涉及特定的遗传异常 将制定抑制异常细胞因子产生的策略 和/或 AML 细胞对细胞因子的异常反应。 这些 策略将在患者身上进行测试，成功的策略将被 在试点临床试验中进行了前瞻性测试。 这里提出的研究 兑现对发展理解的承诺 遗传性异常石对细胞和临床生物学的影响 AML 以及促进发展的承诺 意味着抑制这些异常的生物学后果，以便 从而改善治疗效果。