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: 6459014
• 负责人: HARVEY D PREISLER
• 金额: $ 31.28万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-07 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6459014
• 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致力于研究预后不良的AML及其 从骨髓增生异常状态演变而来 普通分子 将鉴定MDS和AML中存在的遗传异常， 比较，以便AML中存在的异常组合， 在MDS中不能识别。 这些比较将使用两个 策略：患者组的比较和 个体患者从MDS被诊断到 AML出现的时间。 这些研究的目的是 三重：1：开发和确定遗传组合 与AML发展相关的病变2至 确定这些病变对造血细胞的生物学影响;以及 3-将疾病的临床特征及其反应联系起来 基因损伤的治疗及其生物学后果。 设计用于直接检测观察到的 各种观察到的现象之间的关系将是 表现也不错。 在临床层面，我们特别感兴趣的是 作为缓解的原因， 感应失败，也与返回 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 白血病细胞产生的异常细胞因子 对细胞因子产生的异常反应， 存在于AML和MDS中的遗传病变， 在AML的再生长抵抗和早期白血病中起主要作用。 在达到“骨髓增生异常”的患者中白血病复发 AML治疗后缓解。 我们将记录 在这两个过程中涉及特定的遗传异常， 将开发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 将在患者中进行测试，成功的策略将在 在先导性临床试验中进行了前瞻性测试。 这里提出的研究 提出了发展一种理解的承诺， 遗传性铁硼镁石对肿瘤细胞和临床生物学的影响 反洗钱，以及促进发展的承诺， 抑制这些异常的生物学后果， 以改善治疗效果。