SECONDARY HEMATOLOGIC DISORDERS--GENESIS AND TREATMENT

血液学和医学领域面临的主要挑战之一 肿瘤学是指继发性血液疾病的肿瘤学。这些 疾病正变得越来越普遍，至少部分原因是 大剂量细胞毒治疗慢性粒细胞白血病的疗效 患有恶性疾病的患者。高达10%的患者治愈了 用DNA损伤剂治疗的恶性疾病将会发展 一种血液疾病，这一比例在患者中可能是双倍 他们接受自体干细胞移植作为部分 他们的根治疗法。两种继发疾病的快速临床病程 MDS和继发性AML使这些疾病的发展 在已经治愈了一种恶性肿瘤的患者中，尤其令人不安。 虽然有大量关于各种 在MDS和MDS中检测到的分子遗传异常 AML，很少或根本没有关于多久一次的信息 存在多种基因异常，几乎没有信息 关于这些异常的生物后果的现有资料。 这些领域信息的缺乏严重制约了我们的 了解MDS和AML的发展。这些研究 将作为本计划项目的一部分进行，重点是 这些疾病最常见的分子遗传损害将 在同一患者身上同时研究这些损害，活体和 在体外，异常细胞的生物学特性将 识别并与存在的遗传损伤相关。平行 体外研究将有助于确定其背后的机制 联想。将在两个方面特别强调：1- 以5号和/或7号染色体缺失为特征的MDS和AML Q和2-在这些疾病中异常细胞因子的产生和 它在MDS和AML的发生中所起的作用。这两个 特别感兴趣的地区，前者是因为这些地区的稳定性 疾病从MDS向AML强烈演变时的遗传损害 提示这些病变在这些疾病的发生中起着关键作用 第二个是因为我们展示了压制的能力 患者体内细胞因子的异常产生，从而改变 MDS和AML细胞的行为。这种后一种能力提供了 快速将实验室研究结果应用于 临床以改善MDS和AML的治疗结果。

One of the major challenges facing the field of Hematology and Oncology is that of the secondary hematologic disorders. These disorders are becoming increasingly common, at least in part because of the effectiveness of high dose cytotoxic therapy in the treatment of patients with malignant disease. As many as 10% of patients cured of malignant disease by therapy with DNA damaging agents will develop a hematologic disorder and this percentage may be double in patients who are treated with autologous stem cell transplantation as part of their curative therapy. The rapid clinical course of both secondary MDS and secondary AML makes the development of these disorders in patients already cured of one malignancy especially disturbing. While a great deal of information is available regarding a variety of molecular genetic abnormalities which have been detected in MDS and AML, little or no information is available with respect to how often multiple genetic abnormalities are present and little information is available regarding the biological consequences of these abnormalities. The lack of information in these areas severely restricts our understanding of the development of MDS and AML. The studies which will be conducted as part of this Program Project will focus on the most common molecular genetic lesions of these disorders, will study these lesions simultaneously in the same patients, the in vivo and in vitro biological characteristics of the abnormal cells will be identified and related to the genetic lesions which are present. Parallel in vitro studies will help to define the mechanisms underlying these associations. Special emphasis will be placed in two areas: 1 - on MDS and AML characterized by deletions of chromosomes 5 and/or 7 q and 2 - on aberrant cytokine production in these diseases and the role which it plays in the genesis of both MDS and AML. These two areas of particular interest, the former because the stability of these genetic lesions as the disease evolves from MDS to AML strongly suggests a key role of these lesions in the genesis of these disorders and the second because of our demonstrated ability to suppress abnormal cytokine production in vivo in patients and thus alter the behavior of both MDS and AML cells. This later ability offers the prospect of rapidly applying the results of the laboratory studies to the clinic to improve treatment outcome in both MDS and AML.