生物
表观遗传学
髓系白血病
癌症的体细胞进化
表观遗传疗法
免疫学
先天免疫系统
染色质
白血病
癌症研究
免疫系统
遗传学
DNA甲基化
癌症
基因
基因表达
作者
Boyu Cui,Lanlan Ai,Minghui Lei,Yong-Juan Duan,Chao Tang,Jingliao Zhang,Jing Wang,Xuan Li,Caiying Zhu,Yingchi Zhang,Xiaofan Zhu,Tomoya Isobe,Wenyu Yang,Berthold Göttgens,Ping Zhu
出处
期刊:Blood
[American Society of Hematology]
日期:2024-12-11
标识
DOI:10.1182/blood.2024025618
摘要
Pediatric acute myeloid leukemia (pAML) is a clonal disease with recurrent genetic alterations that affect epigenetic states. However, the implications of epigenetic dysregulation in disease progression remain unclear. Here, we interrogated single-cell and clonal level chromatin accessibility of bone marrow samples from 28 pAML patients representing multiple subtypes using mtscATAC-seq, which revealed distinct differentiation hierarchies and abnormal chromatin accessibility in a subtype-specific manner. Innate immune signaling was commonly enhanced across subtypes and related to improved advantage of clonal competition and unfavorable prognosis, with further reinforcement in a relapse-associated leukemia stem cell-like population. We identified a panel of 31 innate immunity related genes to improve the risk classification of pAML patients. By comparing paired diagnosis and post-chemotherapy relapse samples, we showed that primitive cells significantly reduced MHC class II signaling, suggesting an immune evasion mechanism to facilitate their expansion at relapse. Key regulators orchestrating cell cycle dysregulation were identified to contribute to pAML relapse in drug-resistant clones. Our work establishes the single-cell chromatin accessibility landscape at clonal resolution and reveals the critical involvement of epigenetic disruption, offering insights into classification and targeted therapies of pAML patients.
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