复发仍然是治疗失败的一个决定因素，并且是急性髓系白血病 (AML) 患者死亡率的显着原因。尽管人们努力了解 AML 进展和复发机制，但复发中获得性基因突变的研究结果各不相同，这表明固有的遗传异质性，并强调了表观遗传修饰的作用。我们使用 Omni-C、ATAC-seq 和 RNA-seq 对两名成年 AML 患者在诊断和复发时的纵向样本进行了多组学分析。在此，我们描述了 AML 进展中的遗传和表观遗传变化，以阐明复发的潜在机制。差异相互作用分析显示复发样本和诊断样本之间存在显着的 3D 染色质景观重组。比较全局开放染色质图谱表明，复发样本的可访问染色质区域明显少于诊断样本。此外，我们发现与复发相关的上调是通过形成新的活性增强子接触或通过失去与平衡增强子/潜在沉默子的相互作用来实现的。总而言之，我们的研究强调了遗传和表观遗传变化对 AML 进展的影响，强调了多组学方法在理解疾病复发机制和指导潜在治疗干预方面的重要性。版权所有 © 2024 Ahmed、Cavattoni、Villiers、Cugno、Deola 和 Mifsud。

Relapse remains a determinant of treatment failure and contributes significantly to mortality in acute myeloid leukemia (AML) patients. Despite efforts to understand AML progression and relapse mechanisms, findings on acquired gene mutations in relapse vary, suggesting inherent genetic heterogeneity and emphasizing the role of epigenetic modifications. We conducted a multi-omic analysis using Omni-C, ATAC-seq, and RNA-seq on longitudinal samples from two adult AML patients at diagnosis and relapse. Herein, we characterized genetic and epigenetic changes in AML progression to elucidate the underlying mechanisms of relapse. Differential interaction analysis showed significant 3D chromatin landscape reorganization between relapse and diagnosis samples. Comparing global open chromatin profiles revealed that relapse samples had significantly fewer accessible chromatin regions than diagnosis samples. In addition, we discovered that relapse-related upregulation was achieved either by forming new active enhancer contacts or by losing interactions with poised enhancers/potential silencers. Altogether, our study highlights the impact of genetic and epigenetic changes on AML progression, underlining the importance of multi-omic approaches in understanding disease relapse mechanisms and guiding potential therapeutic interventions.Copyright © 2024 Ahmed, Cavattoni, Villiers, Cugno, Deola and Mifsud.