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单细胞转录映射揭示了AML异常分化的遗传和非遗传决定因素

Andy G X Zeng^1,2, Ilaria Iacobucci³, Sayyam Shah¹

¹Princess Margaret Cancer Centre, University Health Network; Toronto, ON, Canada.

bioRxiv : the preprint server for biology

|January 18, 2024

概括

这项研究使用单细胞RNA测序绘制了正常和急性髓性白血病 (AML) 细胞状态的地图. 它揭示了AML中十二种常见的异常分化模式,与特定的遗传突变和不同的细胞起源有关.

科学领域:

血液学血液学血液学
癌症生物学癌症生物学
基因组学就是基因组学.

背景情况:

急性髓性白血病 (AML) 的遗传突变破坏了正常的血细胞发育,导致白血病爆发积累.
了解这些突变如何与细胞起源和分化途径相互作用至关重要,但具有挑战性.
现有的单细胞RNA测序 (scRNA-seq) 应用受到不准确的正常血液形成参考和小患者队列的限制.

研究的目的:

构建人类骨髓血液形成的高分辨率参考地图.
使用此地图,绘制AML,MPAL和AEL细胞状态的地图.
识别AML中的基因型与表型的关联和反复的分化模式.

主要方法:

在55个州生成了263519个人类骨髓造血单细胞转录组的参考地图.
与纯造血干细胞和原生细胞的独立数据集对比这本地图.
应用了该图谱来分析来自318名AML,MPAL和AEL患者样本的120多万个scRNA-seq转录组.

主要成果:

确定了12个反复出现的AML异常分化的模式,汇聚了多种不同的遗传变化.
与非传统的淋巴细胞 (RUNX1) 和红色球体 (TP53) 初始化相关的特定突变.
发现了非遗传决定因素,包括两个KMT2A重新排列的AML亚组,具有明显的白血病干细胞 (LSC) 身份,表明细胞起源多样化.
在患者中观察到共存的LSC等级,为AML演变提供了洞察力.

结论:

正常和恶性细胞状态的精确映射为AML研究和分类提供了一个框架.
这些发现有助于开发针对性治疗血液恶性瘤的向疗法.
该参考地图集增强了scRNA-seq在白血病研究中的应用.

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