文章：

化疗诱导儿童b细胞前体急性淋巴细胞白血病细胞状态的通路化

Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia 

原文发布日期：2021-07-05 

英文摘要：

Comparison of intratumor genetic heterogeneity in cancer at diagnosis and relapse suggests that chemotherapy induces bottleneck selection of subclonal genotypes. However, evolutionary events subsequent to chemotherapy could also explain changes in clonal dominance seen at relapse. We therefore investigated the mechanisms of selection in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) during induction chemotherapy where maximal cytoreduction occurs. To distinguish stochastic versus deterministic events, individual leukemias were transplanted into multiple xenografts and chemotherapy administered. Analyses of the immediate post-treatment leukemic residuum at single-cell resolution revealed that chemotherapy has little impact on genetic heterogeneity. Rather, it acts on extensive, previously unappreciated, transcriptional and epigenetic heterogeneity in BCP-ALL, dramatically reducing the spectrum of cell states represented, leaving a genetically polyclonal but phenotypically uniform population, with hallmark signatures relating to developmental stage, cell cycle and metabolism. Hence, canalization of the cell state accounts for a significant component of bottleneck selection during induction chemotherapy. 

摘要翻译：

比较癌症诊断时和复发时肿瘤内基因异质性可看出化疗导致亚克隆突变体的瓶颈选择。然而，化疗后的进化事件也可能解释复发时集群变化的情况。因此，我们考察了诱导化疗中儿童B细胞前急性淋巴细胞白血病（BCP-ALL）中选择机制。为了区分随机和确定性事件，我们在多例外植株上移植单个白血病细胞，并接受化疗处理。通过单细胞水平分析立即后的残留白血病细胞，发现化疗对基因异质性影响较小。相反，它作用于BCP-ALL中的广泛、 previously unappreciated 的转录和表观遗传异质性，显著减少细胞状态谱系，留下一个基因多克隆但表型一致的群体。其特征标志与发育阶段、细胞周期和代谢有关。因此，诱导化疗中细胞状态的自我调节（canalization）占了瓶颈选择的一个重要组成部分。 

原文链接：

https://www.nature.com/articles/s43018-021-00219-3