儿科急性髓性白血病的克隆进化及其对疾病复发的贡献

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Masayuki Umeda^1,2, Pandurang Kolekar^3,2, Anna Lw Huskey^1,4

¹Department of Pathology, St. Jude Children's Research Hospital, TN.

medRxiv : the preprint server for health sciences

|November 24, 2025

概括

儿科急性髓性白血病 (AML) 复发是由先前存在的亚克隆的选择驱动的,而不是新的突变. 这些亚克隆表现出多样化的转录变化,突出显示了针对干细胞和分化细胞治疗的必要性.

科学领域:

基因组学和分子生物学
儿科瘤学儿科瘤学
癌症遗传学癌症遗传学

背景情况:

复发是儿科急性髓性白血病 (AML) 中的主要死亡原因.
导致AML复发的遗传基础尚未完全理解.
识别复发机制对于改善治愈率至关重要.

研究的目的:

调查与儿科AML复发相关的遗传和转录变化.
确定导致复发的机制,重点关注克隆进化和选择.
确定潜在的治疗点,以预防或治疗AML复发.

主要方法:

来自儿科AML患者的双对诊断复发样本的全基因组和向捕获测序.
纵向深度测序以追踪克隆动态.
用于转录概况的RNA测序和CIBERSORT解卷.
重新分析公开的单细胞RNA测序数据.

主要成果:

突变负担在复发时增加,主要是由于自发的突变发生,与治疗相关的特征很少见.
在复发时,FLT3,WT1和TP53的反复突变得到了丰富,但许多复发的亚克隆携带了非致病变体.
以前存在的亚克隆的克隆选择,而不是复发特异性突变的出现,是复发的主要机制.
转录分析揭示了各种复发轨迹,包括获得干状特征或部分分化,受基线状态的影响.

结论:

儿科AML复发的结果是选择了具有不同进化路径的先前存在的亚克隆.
复发期间的转录进化是异质的,不仅仅是由类似茎的表型驱动的.
针对干细胞样和分化细胞种群对于在儿科AML中实现持久治愈至关重要.

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