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.

中文翻译：

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单细胞表观遗传学和克隆分析可解码儿科急性髓性白血病的疾病进展。


小儿急性髓系白血病 （pAML） 是一种克隆性疾病，具有影响表观遗传状态的复发性基因改变。然而，表观遗传失调对疾病进展的影响仍不清楚。在这里，我们使用 mtscATAC-seq 询问了代表多种亚型的 28 名 pAML 患者骨髓样本的单细胞和克隆水平染色质可及性，以亚型特异性方式揭示了不同的分化层次结构和异常的染色质可及性。先天免疫信号在亚型之间通常增强，并与克隆竞争优势的改善和不良预后有关，在复发相关白血病干细胞样人群中进一步增强。我们确定了一组 31 个先天免疫相关基因，以改善 pAML 患者的风险分类。通过比较配对诊断和化疗后复发样本，我们发现原始细胞显着降低了 MHC II 类信号传导，表明存在免疫逃避机制，可促进它们在复发时扩增。研究发现，协调细胞周期失调的关键调节因子会导致耐药克隆中 pAML 复发。我们的工作在克隆分辨率下建立了单细胞染色质可及性景观，并揭示了表观遗传破坏的关键参与，为 pAML 患者的分类和靶向治疗提供了见解。