Zhu Ming, Zhu Jiali, Zhu Zhijuan, Yang Yiding, Dai Jinxian, Li Hua, Li Nainong, Huang Jialiang
State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China.
Hematopoietic Stem Cell Transplantation Center, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Department of Hematology, Fujian Medical University Union Hospital, No.29 Xinquan Street, Gulou District, Fuzhou, China.
Commun Biol. 2025 May 26;8(1):808. doi: 10.1038/s42003-025-08257-8.
Mutations and gene rearrangements are crucial for the diagnosis and subtyping of acute myeloid leukemia (AML). However, the contribution of non-coding genetic variants, particularly those within cis-regulatory elements (CREs), to AML pathophysiology and heterogeneity remains poorly understood. In this study, we characterize the single-cell chromatin accessibility landscapes of 10 bone marrow samples from AML patients at diagnosis. Additionally, we develop eMut, an integrated computational pipeline for detecting, imputing, and functionally characterizing non-coding mutations in CREs at the single-cell level. Our analysis identifies 2878 potential somatic non-coding mutations, highlighting the extensive mutational heterogeneity in the non-coding genome of AML patients, with recurrent non-coding mutations displaying cell type-specific patterns. We show that mutated CREs are enriched with blood-related genetic variants, potentially linked to AML-associated genes, and harbor a higher abundance of functional CREs, suggesting their functional relevance in leukemogenesis. Importantly, we pinpoint candidate functional non-coding mutations that associate with alteration of target gene expression in AML. Collectively, our work provides a comprehensive resource of single-cell chromatin accessibility in AML and introduces an integrative approach to identify candidate functional non-coding mutations contributing to cellular heterogeneity in AML.
突变和基因重排对于急性髓系白血病（AML）的诊断和亚型分型至关重要。然而，非编码基因变异，尤其是顺式调控元件（CREs）内的变异，对AML病理生理学和异质性的贡献仍知之甚少。在本研究中，我们描绘了10例AML患者诊断时骨髓样本的单细胞染色质可及性图谱。此外，我们开发了eMut，这是一种用于在单细胞水平检测、推断和功能表征CREs中非编码突变的综合计算流程。我们的分析确定了2878个潜在的体细胞非编码突变，突出了AML患者非编码基因组中广泛的突变异质性，其中反复出现的非编码突变呈现出细胞类型特异性模式。我们表明，突变的CREs富含与血液相关的基因变异，可能与AML相关基因有关，并且含有更高丰度的功能性CREs，表明它们在白血病发生中的功能相关性。重要的是，我们确定了与AML中靶基因表达改变相关的候选功能性非编码突变。总体而言，我们的工作提供了AML中单细胞染色质可及性的全面资源，并引入了一种综合方法来识别导致AML细胞异质性的候选功能性非编码突变。
