Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level
Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level
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DOI：
10.1038/s41591-018-0267-4
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发表时间：
2019-01-01
期刊：
影响因子：
82.9
通讯作者：
Steidl, Ulrich
中科院分区：
文献类型：
--
作者：
Chen, Jiahao;Kao, Yun-Ruei;Steidl, Ulrich
骨髓增生异常综合征（MDS）经常进展为急性骨髓性白血病（AML）;然而，导致恶变的细胞尚未直接阐明。由于人类MDS向AML的进展提供了一个确定肿瘤转化的细胞起源和机制的生物学系统，我们研究了进展为AML的MDS患者纵向样本中高度分离的干细胞群。靶向深度测序结合分选细胞群的单细胞测序显示，MDS阶段的干细胞，包括免疫表型和功能定义的前MDS干细胞（pre-MDS-SC），与原始细胞相比具有显著更高的亚克隆复杂性，并含有大量衰老相关的变异体。高度分离的干细胞的单细胞靶向重测序揭示了非线性、平行克隆进化的模式，前MDS-SC和MDS-SC内的不同亚克隆分别促成MDS原始细胞的产生或向AML的进展。此外，表型异常的干细胞克隆在转化过程中扩增，在MDS原始细胞中检测不到的干细胞亚克隆在AML进展时占主导地位。这些结果揭示了在MDS进展为AML过程中不同干细胞区室的关键作用，并对目前以大量细胞为中心的精确肿瘤学方法具有影响，无论是在MDS还是从癌前病变演变而来的可能其他癌症中，这些方法可能会错过驱动疾病进展和白血病转化的预先存在的罕见异常干细胞。
Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immuno-phenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants. Single-cell targeted resequencing of highly fractionated stem cells revealed a pattern of nonlinear, parallel clonal evolution, with distinct subclones within pre-MDS-SC and MDS-SC contributing to generation of MDS blasts or progression to AML, respectively. Furthermore, phenotypically aberrant stem cell clones expanded during transformation and stem cell subclones that were not detectable in MDS blasts became dominant upon AML progression. These results reveal a crucial role of diverse stem cell compartments during MDS progression to AML and have implications for current bulk cell-focused precision oncology approaches, both in MDS and possibly other cancers that evolve from premalignant conditions, that may miss pre-existing rare aberrant stem cells that drive disease progression and leukemic transformation.