Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Department of Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL), University of Heidelberg, 69117 Heidelberg, Germany.
Cell Stem Cell. 2023 May 4;30(5):706-721.e8. doi: 10.1016/j.stem.2023.04.001. Epub 2023 Apr 24.
Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.
患者间的变异性和健康与白血病干细胞（LSCs）的相似性阻碍了对急性髓细胞白血病（AML）中 LSCs 的特征描述及其分化景观的研究。在这里，我们引入了 CloneTracer，这是一种将克隆分辨率添加到单细胞 RNA-seq 数据集中的新方法。将该方法应用于 19 名 AML 患者的样本中，CloneTracer 揭示了白血病分化的途径。尽管残留的健康和前白血病细胞主导了休眠干细胞隔室，但活跃的 LSCs 与其健康对应物相似，并保留了红系能力。相比之下，下游髓样祖细胞构成了一个高度异常的、定义疾病的隔室：它们的基因表达和分化状态影响了化疗反应和白血病分化为转录正常单核细胞的能力。最后，我们证明了 CloneTracer 识别在白血病细胞中特异性失调的表面标志物的潜力。总之，CloneTracer 揭示了一种与健康细胞相似的分化景观，可能决定 AML 的生物学和治疗反应。
