MDS EVOLUTION TO AML--MOLECULAR BIOLOGY AND CYTOKINES

项目III致力于研究预后不良的急性髓系白血病及其 从骨髓发育异常状态进化而来。常见的分子 MDS和AML中存在的遗传异常将被识别并 相比较而言，急性髓细胞白血病中存在的异常组合 不在MDS中可以被识别。这些比较将利用两个 策略：两组患者的比较和一系列研究 从MDS确诊之日起至 急性髓系白血病出现的时间。这些研究的目标是 三重：1：开发和鉴定遗传组合 与AML 2-TO发展相关的损害 确定这些损伤对造血细胞的生物学影响；以及 3-描述疾病的临床特征及其反应 对遗传损伤及其生物学后果的治疗。 专门的体外研究，旨在直接测试观察到的 各种观察到的现象之间的关系将是 表现也很好。在临床层面上，我们特别感兴趣 在作为缓解原因的再生抵抗现象中 诱导失败，而且还在关联中返回 治疗后的骨髓增生性造血障碍[而不是白血病 或正常细胞]，白血病缓解时间较短。我们假设 白血病细胞产生的异常细胞因子与 对细胞因子产生的异常反应，都是由于 AML和MDS中存在的遗传损害起到了 在急性髓系白血病再生长耐药中的主要作用 骨髓增生异常患者的白血病复发 急性髓系白血病治疗后缓解。我们将记录 特定的遗传异常参与了这两个过程和 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 这些策略将在患者身上进行测试，成功的策略将是 在试点临床试验中进行了前瞻性测试。在这里提出的研究 坚持对发展的认识的承诺 遗传无角闪石对人骨肉瘤细胞和临床生物学的影响 并承诺促进 抑制这些异常的生物后果的手段 以改善治疗结果。

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.