Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee.
Department of Pathology, Microbiology, and Immunology, VUMC, Nashville, Tennessee.
Blood Cancer Discov. 2022 Jul 6;3(4):316-329. doi: 10.1158/2643-3230.BCD-21-0128.
Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications.
Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level. See related article by Menssen et al., p. 330 (31). See related commentary by Romine and van Galen, p. 270. This article is highlighted in the In This Issue feature, p. 265.
骨髓增生异常综合征（MDS）中的克隆进化可导致临床进展和继发性急性髓系白血病（sAML）。为了剖析与这种进展相关的克隆结构变化，我们对 18 名患者的 MDS 和 sAML 配对样本进行了单细胞基因分型。单细胞基因型分析揭示了患者特异性的克隆进化，并能够评估单细胞突变的共同发生。我们发现，克隆结构的变化通过不同的模式进行，分为静态或动态，其中动态克隆结构通过 blast 计数倍数变化具有更增殖的表型。对部分患者的蛋白质基因组分析证实，致病性突变主要局限于原始和成熟的髓样细胞，但我们也鉴定出淋巴细胞亚群中罕见但存在的突变。配对样本集的单细胞转录组分析进一步确定了两个进展病例中涉及的基因集和信号通路。这些数据共同定义了 MDS 克隆景观的连续变化，具有临床和治疗意义。
单细胞基因组测序使 MDS 进展中的精确克隆轨迹成为可能。在这里，我们使用这项技术揭示了驱动向继发性 AML 转化的克隆结构和克隆进化模式。我们进一步在单细胞水平上定义疾病进展的表型和转录变化。请参阅 Menssen 等人在本期第 330 页（31）的相关文章。请参阅 Romine 和 van Galen 在第 270 页的相关评论。本文在本期的重点介绍特色中，第 265 页。
