STEM CELL PROGNOSTICATORS IN MYELODYSPLASTIC SYNDROMES

骨髓增生异常综合征（MDS）是一种异质性疾病， 治疗结果可变的造血。患者分层 根据细胞学、细胞遗传学或细胞功能标准， 不能一致地预测疾病进展或治疗反应。 改进的分类将有助于患者分层， 最终实现患者个体化治疗。我们建议探索 治疗反应和缓解持续时间可能 至少部分地通过以下的频率和增殖分数来确定： 表型确定的骨髓干细胞中的遗传异常细胞 隔间我们预测，MDS与干细胞的参与， 在治疗前检测到，那些具有低增殖性的患者 一部分遗传异常的干细胞将对 化疗比那些具有高增殖分数。此外，委员会认为， 我们假设缓解持续时间与以下频率密切相关： 残留的异常细胞及其增殖和克隆形成特性。 我们将在G-CSF的临床试验中检验这些假设， 通过流式细胞术和分选， 溴脱氧尿苷掺入的免疫荧光连接分析 DNA、克隆形成试验和荧光原位杂交（FISH）， 测量遗传异常干细胞的增殖分数 亚群具体而言，我们将： 1)确定是否频率和增殖分数的 细胞遗传学异常干细胞有助于缓解 诱导 2)确定缓解持续时间是否与频率相关， 缓解期遗传异常干细胞的增殖分数 骨髓 3)确定残留的遗传物质的克隆形成潜力 异常细胞对缓解持续时间有明显影响。 我们预计这些数据将有助于治疗反应 并促进高危MDS患者的治疗监测。

Myelodysplastic syndrome (MDS) is a heterogeneous disease of ineffective hemopoiesis with variable treatment outcome. Stratification of patients according to cytologic, cytogenetic, or cellular functional criteria does not consistently predict disease progression or treatment response. Improved prognostication would facilitate patient stratification and may ultimately lead to individualized patient treatment. We propose to explore the possibility that response to therapy and remission duration are determined, at least in part, by frequency and proliferative fraction of genetically aberrant cells in phenotypically-defined marrow stem cell compartments. We predict that MDS with stem cell involvement can be detected prior to therapy and that those patients with a low proliferative fraction of genetically aberrant stem cells will respond less well to chemotherapy than those with a high proliferative fraction. Furthermore, we postulate that remission duration is closely linked to the frequency of residual aberrant cells and their proliferative and clonogenic properties. We will test these hypotheses in a clinical trial of G-CSF and chemotherapy for high risk MDS by using flow cytometry and sorting, immunofluorescence-linked analyses of bromodeoxuridine incorporation into DNA, clonogenic assays and fluorescence in situ hybridization (FISH) to measure the proliferative fraction of genetically-aberrant stem cell subpopulations. Specifically, we will: 1)Determine whether the frequency and proliferative fraction of cytogenetically aberrant stem cells prognosticates for remission induction. 2) Determine whether remission duration correlates with the frequency-and proliferative fraction of genetically aberrant stem cells in remission marrow. 3) Determine whether the clonogenic potential of residual genetically aberrant cells prognosticates for remission duration. We anticipate that these data will prognosticate for treatment response and facilitate treatment monitoring in high risk MDS patients.