Clinical and Molecular Heterogeneity in the Myelodysplastic Syndromes

摘要 MDS代表一组由造血干细胞引起的获得性骨髓衰竭综合征 (HSCs)。虽然大多数MDS患者经历进行性细胞减少症，但相当少数(30%)将会进展 急性髓系白血病(AML)；然而，决定患者是否经历 进行性血细胞减少症或白血病转化目前知之甚少。而MDS的无效性 治疗是由于他们无法有效地消除MDS克隆和/或恢复正常分化，它 目前尚不清楚去甲基化药物(HMAs)是否作用于HSC或承诺的祖细胞来诱导 血液学改善和/或原始细胞计数减少，或者如果HMA通过类似或独特的机制发挥作用 在这些不同的细胞群中。我们和其他人已经表明MDS HSCs表现出明显不同的基因 CD34+造血干/祖细胞(HSPC)的表达谱以及它们在基因上的 和转录异质性6-10；然而，这些先前的研究并不是专门设计来捕捉 致力于祖细胞对疾病进展或对HMAS的治疗反应的贡献。我们假设 患有进行性红细胞减少症的MDS患者的造血干细胞和承诺的祖细胞 白血病转化在HMA之前和对HMA的反应中表现出独特的转录特征 心理治疗。其次，我们假设HMAS引起独特的转录和功能变化 在MDS造血干细胞和忠诚的祖细胞中，以及他们诱导特定转录的能力 计划决定患者是否对血液系统的改善和/或原始细胞作出反应 减税。我们建议阐明HSC的转录基础和承诺的祖细胞反应 在单细胞水平上使用新的全长cDNAscRNA-seq技术的MDS患者将能够 配对Pre-Pre的单个细胞内转录组和突变数据的同时特征 以及来自不同类型疾病进展和对HMA反应的MDS患者的治疗后样本 心理治疗。我们还将通过评估MDS相关的RNA特征来评估我们的发现的临床相关性。 在转录组数据和临床结果数据可用的MDS患者的较大队列中。 将使用小鼠评估异常转录本对MDS进展的贡献 MDS模型以及原代MDS患者细胞。总体而言，我们希望我们的研究：1)识别基因 以及决定MDS患者是否会经历进行性细胞减少症的生物学途径 白血病转化；2)阐明不同HSPC人群在决定临床反应中的作用 HMA治疗；3)寻找新的生物标志物用于预测临床结果和治疗反应 MDS；4)为未来新途径或基因靶向的临床研究提供生物学基础 与HMAS相结合的代理。

SUMMARY MDS represents a group of acquired bone marrow failure syndromes arising from hematopoietic stem cells (HSCs). While most MDS patients experience progressive cytopenias, a significant minority (30%) will progress to acute myeloid leukemia (AML); however, the mechanisms that determine whether patients experience progressive cytopenias or leukemia transformation are poorly understood. While the ineffectiveness of MDS therapies is due to their inability to effectively eliminate MDS clones and/or restore normal differentiation, it remains unclear whether hypomethylating agents (HMAs) act on HSCs or committed progenitors to induce hematologic improvement and/or reductions in blast count, or if HMAs act through similar or unique mechanisms in these distinct cell populations. We and others have shown that MDS HSCs exhibit markedly different gene expression profiles than CD34+ hematopoietic stem/progenitor cells (HSPCs) and that they are also genetically and transcriptionally heterogeneous6-10; however, these prior studies were not designed to specifically capture committed progenitor contributions to disease progression or therapeutic responses to HMAs. We hypothesize that HSCs and committed progenitors from MDS patients who experience progressive cytopenias or leukemic transformation exhibit unique transcriptional signatures prior to, and in response to, HMA therapy. Secondarily, we hypothesize that HMAs induce unique transcriptional and functional changes in MDS HSCs and committed progenitors, and that their ability to induce specific transcriptional programs determines whether or not patients respond with hematologic improvements and/or blast reductions. We propose to elucidate the transcriptional basis of HSC and committed progenitor responses from MDS patients at the single cell level using novel full-length cDNA scRNA-seq technologies that will allow simultaneous characterization of the transcriptome and mutational data within individual cells from paired pre- and post-therapy samples from MDS patients with different types of disease progression and responses to HMA therapy. We also will evaluate the clinical relevance of our findings by evaluating MDS-associated RNA features in larger cohorts of MDS patients for whom transcriptome data and clinical outcome data are available. Assessments of the contribution of dysregulated transcripts to MDS progression will be evaluated using mouse models of MDS as well as primary MDS patient cells. Overall, we expect our studies to: 1) Identify the genes and biological pathways that determine whether MDS patients will experience progressive cytopenia versus leukemic transformation; 2) Elucidate the roles of different HSPC populations in determining clinical responses to HMA therapy; 3) Identify novel biomarkers for prognostication of clinical outcomes and therapy responses in MDS; 4) Provide the biological rationale for future clinical studies of novel pathway- or genetically-targeted agents in combination with HMAs.