Single-cell epigenetic and clonal analysis decodes disease progression in pediatric acute myeloid leukemia
Abstract
Abstract 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 patients with pAML representing multiple subtypes using mitochondrial single-cell assay for transposase-accessible chromatin with sequencing, 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 patients with pAML. By comparing paired diagnosis and postchemotherapy relapse samples, we showed that primitive cells significantly reduced major histocompatibility complex 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 patients with pAML.
Article Details
Authors (15)
Boyu Cui
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Lanlan Ai
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Minghui Lei
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yongjuan Duan
1Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Chao Tang
Jingliao Zhang
1Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yan Gao
Xuan Li
Department of Chemistry
Caiying Zhu
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yingchi Zhang
Xiaofan Zhu
Tomoya Isobe
Wenyu Yang
Laboratory of Advanced Materials, Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials (2011-iChEM), College of Chemistry and Materials
Berthold Göttgens
Ping Zhu