祖细胞
髓系白血病
髓样
干细胞
生物
染色质
谱系(遗传)
细胞疗法
癌症研究
免疫学
遗传学
基因
作者
Huihui Fan,Feng Wang,Andy G.X. Zeng,Alex Murison,Katarzyna Tomczak,Dapeng Hao,Fatima Zahra Jelloul,Bofei Wang,Praveen Barrodia,Shaoheng Liang,Ken Chen,Linghua Wang,Zhongming Zhao,Kunal Rai,Abhinav K. Jain,John E. Dick,Naval Daver,Andrew Futreal,Hussein A. Abbas
标识
DOI:10.1038/s42003-023-05120-6
摘要
Abstract Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of therapy resistance. Since the cell of origin can impact response to therapy, it is crucial to understand the lineage composition of AML cells at time of therapy resistance. Here we leverage single-cell chromatin accessibility profiling of 22 AML bone marrow aspirates from eight patients at time of therapy resistance and following subsequent therapy to characterize their lineage landscape. Our findings reveal a complex lineage architecture of therapy-resistant AML cells that are primed for stem and progenitor lineages and spanning quiescent, activated and late stem cell/progenitor states. Remarkably, therapy-resistant AML cells are also composed of cells primed for differentiated myeloid, erythroid and even lymphoid lineages. The heterogeneous lineage composition persists following subsequent therapy, with early progenitor-driven features marking unfavorable prognosis in The Cancer Genome Atlas AML cohort. Pseudotime analysis further confirms the vast degree of heterogeneity driven by the dynamic changes in chromatin accessibility. Our findings suggest that therapy-resistant AML cells are characterized not only by stem and progenitor states, but also by a continuum of differentiated cellular lineages. The heterogeneity in lineages likely contributes to their therapy resistance by harboring different degrees of lineage-specific susceptibilities to therapy.
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