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  3. Dynamic heterogeneity towards drug resistance in AML cells is primarily driven by epigenomic mechanism unveiled by multi-omics analysis

Dynamic heterogeneity towards drug resistance in AML cells is primarily driven by epigenomic mechanism unveiled by multi-omics analysis

  • J Adv Res. 2025 May 21:S2090-1232(25)00358-3. doi: 10.1016/j.jare.2025.05.038.
Yulong Zhang 1,  Yanfang Lu 2,  Liyao Mai 3,  Zebin Wen 4,  Min Dai 5,  Siwen Xu 4,  Xianwei Lin 6,  Yongjian Luo 6,  Yinbin Qiu 4,  Yuting Chen 1,  Zhanying Dong 4,  Caiming Chen 1,  Wei Meng 4,  Xingguang Luo 7,  Guanchuan Lin 8,  Paul K H Tam 9,  Xinghua Pan 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, School of Basic Medical Sciences, Guangzhou, Guangdong, China; Precision Regenerative Medicine Research Centre, Medical Science Division, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China.
  • 2 Department of Biochemistry and Molecular Biology, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, School of Basic Medical Sciences, Guangzhou, Guangdong, China; Department of Nephrology, Henan Provincial Key Laboratory of Kidney Disease and Immunology, Henan International Joint Laboratory of Kidney Disease and Microenvironment, Henan Provincial Clinical Research Center for Kidney Disease, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Henan 450053, China.
  • 3 Department of Biochemistry and Molecular Biology, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, School of Basic Medical Sciences, Guangzhou, Guangdong, China; Key Laboratory of Conservation and Application in Biodiversity of South China, School of Life Sciences, Guangzhou University, Guangzhou, Guangdong, China.
  • 4 Department of Biochemistry and Molecular Biology, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, School of Basic Medical Sciences, Guangzhou, Guangdong, China.
  • 5 Institute of Genetics and Developmental Biology, Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China; University of the Chinese Academy of Sciences, Beijing, China.
  • 6 SequMed Institute of Biomedical Sciences, Guangzhou 510530 Guangdong Province, China.
  • 7 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
  • 8 Department of Biochemistry and Molecular Biology, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, School of Basic Medical Sciences, Guangzhou, Guangdong, China. Electronic address: lyncelot.lin@qq.com.
  • 9 Precision Regenerative Medicine Research Centre, Medical Science Division, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China. Electronic address: pkhtam@must.edu.mo.
  • 10 Department of Biochemistry and Molecular Biology, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, School of Basic Medical Sciences, Guangzhou, Guangdong, China; Precision Regenerative Medicine Research Centre, Medical Science Division, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao 999078, China; Key Laboratory of Infectious Diseases Research in South China (China Ministry Education), Southern Medical University, Guangzhou, Guangdong 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong Province 510515, China. Electronic address: panxinghua@must.edu.mo.
PMID: 40409464 DOI: 10.1016/j.jare.2025.05.038
Abstract

Introduction: Acute myeloid leukemia (AML) is a hematologic malignancy characterized by aggressive proliferation and chemoresistance, leading to poor patient outcomes. Despite advances in chemotherapy, resistance mechanisms remain inadequately understood, particularly at the cellular and molecular level.

Objectives: This study aims to elucidate the cellular and molecular mechanisms underlying drug resistance in AML cells.

Methods: A multi-omics approach was employed, integrating single-cell RNA Sequencing (scRNA-seq), chromatin accessibility profiling (scATAC-seq), DNA methylation analysis, and whole-exome Sequencing (WES). AML cell lines (KG-1a, Kasumi-1, and HL-60) were treated with standard chemotherapeutic agents, including cytarabine (Ara-C), daunorubicin (DNR), azacitidine (AZA), and decitabine (DEC). Additionally, we developed a novel multiplexed scRNA-seq strategy, NAMUL-seq, to enhance the efficiency and scalability of single-cell transcriptomic research.

Results: We observed substantial cellular heterogeneity and dynamic transcriptomic trajectories in AML cells subjected to various treatments, uncovering a tendency for reprogramming towards a more stem-like state. Notably, Ara-C-resistant KG-1a cells predominantly originated from G2/M phase subpopulations, suggesting a resistance mechanism linked to specific cell cycle stages. Our findings further indicate that rapid Ara-C resistance is primarily driven by epigenomic changes, including alterations in DNA methylation, chromatin architecture, and transcription factor activity, whereas exonic mutations played a minimal role.

Conclusion: This study demonstrates that AML drug resistance is predominantly driven by epigenomic mechanisms rather than genetic mutations. This study provides a detailed cellular and molecular characterization of AML drug response and resistance, identifying potential therapeutic targets and laying the groundwork for future efforts to overcome chemoresistance.

Keywords

Acute myeloid leukemia; Drug resistance; Multi-omics; Sample multiplexing; Single-cell sequencing.

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