STEM CELL PROGNOSTICATORS IN MYELODYSPLASTIC SYNDROMES

骨髓增生异常综合征(MDS)是一种疗效不佳的异质性疾病 治疗结果不同的造血功能。病人的分层 根据细胞学、细胞遗传学或细胞功能标准 不能始终如一地预测疾病进展或治疗反应。 改进的预测将有助于患者分层，并可能 最终导致患者的个体化治疗。我们建议探索 治疗反应和缓解时间的可能性是 至少部分地由频率和增殖比例决定 表型定义的骨髓干细胞中的遗传异常细胞 车厢。我们预测有干细胞参与的MDS可能是 在治疗前检测到，那些低增殖率的患者 部分基因异常的干细胞对 化疗比那些高增殖率的患者要好。此外， 我们假设缓解期与以下因素密切相关 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 流式细胞术与分选联合化疗治疗高危MDS 溴脱氧尿嘧啶核苷掺入的免疫荧光分析 DNA、克隆形成试验和荧光原位杂交 检测基因异常干细胞的增殖率 亚群。具体来说，我们会： 1)确定肿瘤的发生频率和增殖率 细胞遗传学异常的干细胞预测缓解 归纳法。 2)确定缓解期是否与频率相关-以及 缓解期基因异常干细胞的增殖率 骨髓。 3)确定残存细胞的克隆形成潜能是否遗传 异常细胞可预测缓解期。 我们预计这些数据将预测治疗反应。 并促进对高危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.