Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML

作者：Yongping Zhang, Shuting Jiang, Fuhong He, Yuanyuan Tian, Hai Hu, Lijun Gao, Zhang Li, Aili Chen, Yixin Hu, Liyan Fan, Chun Yang, Bi Zhou, Dan Liu, Zihan Zhou, Yanxun Su, Lei Qin, Yi Wang, Hailong He, Jun Lü, Peifang Xiao, Shaoyan Hu, Qian‐Fei Wang · 发表于：Genome biology · 年份：2023 · DOI：10.1186/s13059-023-03031-7 · 被引用次数：61 · 研究领域：Acute Myeloid Leukemia Research、Hematopoietic Stem Cell Transplantation、Single-cell and spatial transcriptomics

Abstract Background Cancer patients can achieve dramatic responses to chemotherapy yet retain resistant tumor cells, which ultimately results in relapse. Although xenograft model studies have identified several cellular and molecular features that are associated with chemoresistance in acute myeloid leukemia (AML), to what extent AML patients exhibit these properties remains largely unknown. Results We apply single-cell RNA sequencing to paired pre- and post-chemotherapy whole bone marrow samples obtained from 13 pediatric AML patients who had achieved disease remission, and distinguish AML clusters from normal cells based on their unique transcriptomic profiles. Approximately 50% of leukemic stem and progenitor populations actively express leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures, respectively. These clusters have a higher chance of tolerating therapy and exhibit an enhanced metabolic program in response to treatment. Interestingly, the transmembrane receptor CD69 is highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (named the CD69 + HSC-like subpopulation). Furthermore, overexpression of CD69 results in suppression of the mTOR signaling pathway and promotion of cell quiescence and adhesion in vitro. Finally, the presence of CD69 + HSC-like cells is associated with unfavorable genetic mutations, the persistence of residual tumor cells in chemotherapy, and poor outcomes in independent pediatric and adult public...