Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity
Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity
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DOI：
10.1016/j.cell.2019.01.031
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发表时间：
2019-03-07
期刊：
影响因子：
64.5
通讯作者：
Bernstein, Bradley E.
中科院分区：
文献类型：
--
作者：
van Galen, Peter;Hovestadt, Volker;Bernstein, Bradley E.
急性髓性白血病（AML）是一种异质性疾病，存在于复杂的微环境中，使理解不同细胞类型如何促进疾病进展的努力变得复杂。我们将单细胞RNA测序和基因分型相结合，对来自40份骨髓穿刺液的38，410个细胞进行了分析，其中包括16名AML患者和5名健康供体。然后，我们应用机器学习分类器来区分一系列恶性细胞类型，这些恶性细胞类型的丰度在患者之间和同一肿瘤中的亚克隆之间变化。细胞类型组合物与原型遗传病变相关，包括FLT 3-ITD与丰富的祖细胞样细胞的关联。原始AML细胞表现出与干细胞和髓样启动基因共表达的转录程序失调，并具有预后意义。分化的单核细胞样AML细胞表达不同的免疫调节基因，并在体外抑制T细胞活性。总之，我们提供了单细胞技术和AML细胞状态，调节剂和标记物的图谱，对精准医学和免疫疗法有影响。
Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T cell activity in vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies.