Abstract 2749: Single-cell 3D genome structure analysis reveals clonal evolution and heterogeneity in acute myeloid leukemia

Abstract Alterations in the 3D genome organization have been reported in different types of cancer and have been linked with gene dysregulation and cancer progression. However, majority of the studies were performed using bulk chromatin interaction assays and therefore, cannot address the heterogeneity and clone evolution in primary human tumors. In this study, we generated single cell Hi-C and single cell ATAC-Seq data in a cohort of AML patients, comprising samples at different disease stages, including diagnosis, remission, and relapse. To our knowledge, this is first large collection of single cell Hi-C data in primary tumor. In total, we profiled 153,517 cells across 13 samples, revealing distinct contact patterns and significant heterogeneity in genome-wide contact features between different samples, as well as within the same sample. We demonstrated the impact of 3D genome alterations on AML-specific gene expression programs, highlighting the role of compartmentalization in driving AML pathogenesis. Moreover, we identified hundreds of AML-specific chromatin domains with decreased heterogeneity during the transition from initial diagnosis to post-treatment relapse, suggesting the emergence and expansion of therapy-resistant subclones. By integrating a clonal evolution model, we delineated the dynamic relationship between somatic mutation, structural variation, and 3D genome architecture alterations. Finally, we discovered a chromatin loop uniquely present in a subclone of the relapse sample, which hijacked a distal enhancer to the known chemo-resistance-related oncogene and led to its upregulation. To summarize, our findings demonstrated the heterogeneity of 3D genome structure in AML and provide insights on the disease progression and relapse mechanisms. Citation Format: Yu Luan, Ye Hou, Yutong Lei, Qiushi Jin, Jie Xu, Bei Jia, Siwei Xu, Ping Wang, Alok Swaroop, Yihao Fu, Juan Wang, Qixuan Wang, Hong Zheng, Jing Zhang, Feng Yue. Single-cell 3D genome structure analysis reveals clonal evolution and heterogeneity in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2749.