Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.
Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.
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DOI：
10.1186/s13059-023-03031-7
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发表时间：
2023-08-31
期刊：
影响因子：
12.3
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中科院分区：
文献类型：
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癌症患者可以对化疗产生显著的反应，但仍保留耐药肿瘤细胞，最终导致复发。尽管异种移植模型研究已经确定了与急性髓系白血病（AML）化疗耐药性相关的几种细胞和分子特征，但AML患者在多大程度上表现出这些特性仍然很大程度上未知。我们将单细胞RNA测序应用于从13名已获得疾病缓解的儿科急性髓细胞白血病患者中获得的成对化疗前和化疗后全骨髓样本，并根据其独特的转录组学特征将急性髓细胞白血病簇与正常细胞区分开来。大约50%的白血病干细胞和祖细胞群体分别活跃地表达白血病干细胞（LSC）和氧化磷酸化（OXPHOS）特征。这些簇具有更高的耐受治疗的机会，并且表现出响应于治疗的增强的代谢程序。有趣的是，跨膜受体CD 69在化学抗性造血干细胞（HSC）样群体（称为CD 69 + HSC样亚群）中高度表达。此外，在体外，CD 69的过表达导致mTOR信号传导途径的抑制和细胞静止和粘附的促进。最后，CD 69 + HSC样细胞的存在与不利的基因突变、化疗中残留肿瘤细胞的持续存在以及独立的儿科和成人AML队列的不良结局相关。我们的分析揭示了白血病干细胞和OXPHOS是人类AML患者的两个主要化疗耐药特征。CD 69可能作为一个潜在的生物标志物，在确定一个亚群的化疗耐药白血病干细胞。这些发现对于靶向残留的化疗存活的AML细胞具有重要意义。在线版本包含补充材料，可通过10.1186/s13059-023-03031-7获得。
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. The online version contains supplementary material available at 10.1186/s13059-023-03031-7.
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生态原理遇上癌症治疗：小剂量化疗治疗儿童急性髓系白血病
影响因子：
20.6
作者：
Hu Y;Chen A;Zheng X;Lu J;He H;Yang J;Zhang Y;Sui P;Yang J;He F;Wang Y;Xiao P;Liu X;Zhou Y;Pei D;Cheng C;Ribeiro RC;Hu S;Wang QF
通讯作者：
Wang QF
DOI：
10.3324/haematol.2011.052829
发表时间：
2012-02-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
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作者：
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通讯作者：
Amadori, Sergio
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
11.4
作者：
Costello, RT;Mallet, F;Olive, D
通讯作者：
Olive, D
影响因子：
20.3
作者：
Ho, Tzu-Chieh;LaMere, Mark;Becker, Michael W.
通讯作者：
Becker, Michael W.