癌症患者在化疗过程中可能取得显著疗效，但仍保留耐药肿瘤细胞，最终导致复发。尽管异种移植模型的研究发现了与急性髓系白血病（AML）耐药性相关的一些细胞和分子特征，但AML患者在多大程度上表现出这些特征还大多未知。本研究使用单细胞RNA测序技术对来自13名儿童AML患者的成对化疗前后的全骨髓样品进行分析，通过其独特的转录组特征将AML细胞簇与正常细胞区分开来。约50%的白血病干细胞和祖细胞群体分别主动表达白血病干细胞（LSC）和氧化磷酸化（OXPHOS）信号。这些细胞簇更有可能耐受治疗，并对治疗产生增强的代谢适应。有趣的是，跨膜受体CD69在耐药造血干细胞（HSC）样群体（命名为CD69+ HSC-like亚群）中高表达。此外，CD69的过表达会抑制mTOR信号通路，在体外促进细胞静止和粘附。最后，CD69+ HSC-like细胞的存在与不利的遗传突变、化疗后残留肿瘤细胞的持续存在以及独立儿童和成人AML群体中的不良结果相关。我们的分析揭示了AML患者中的白血病干细胞和OXPHOS作为两个主要的耐药特征。CD69可能作为定义一种耐药白血病干细胞亚群的潜在生物标志物。这些发现对于靶向残存的化疗存活AML细胞具有重要意义。© 2023年 Springer Nature旗下的BioMed Central Ltd.

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.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 AML cohorts.Our analysis reveals leukemia stem cell and OXPHOS as two major chemoresistant features in human AML patients. CD69 may serve as a potential biomarker in defining a subpopulation of chemoresistant leukemia stem cells. These findings have important implications for targeting residual chemo-surviving AML cells.© 2023. BioMed Central Ltd., part of Springer Nature.