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Background <p>Comprehensive analysis of single-cell transcriptome and chromatin accessibility will contribute to interpret the heterogeneity of acute myeloid leukemia (AML). We hypothesize that integrating single-cell transcriptomic and chromatin accessibility landscapes underlying t(8;21) AML will provide valuable insights into its heterogeneous cellular properties and gene regulatory programs.</p> Methods <p>Here, we conducted paired single-cell RNA-sequencing (scRNA-seq) and single-cell ATAC sequencing on bone marrow samples from newly diagnosed t(8;21) AML patients and healthy controls. Genetic signatures extracted from scRNA-seq were built and validated across three independent cohorts (German AMLCG1999, GSE106291 and TCGA LAML).</p> Results <p>We identified <i>TCF12</i>, a core component of AML1-ETO-containing transcription factor complex (AETFC), as the most active transcription factor in blast cells, driving a universally repressed chromatin state. Furthermore, we delineated two functionally distinct T cell subsets, revealing that <i>EOMES</i>-mediated transcriptional regulation promotes the expansion of a cytotoxic T cell population (T cells_2; high <i>GNLY</i>, <i>NKG7</i> and <i>GZMB</i> expression), with an increased clonality and a tendency for drug resistance. In addition, we discovered a novel leukemic CMP-like cluster characterized by high <i>TPSAB1</i>, <i>HPGD</i> and <i>FCER1A</i> expression. Leveraging machine learning-based integration of multi-omic profiles, we identified a robust 9-gene prognostic signature, which demonstrated significant predictive value for AML outcomes across three independent cohorts.</p> Conclusions <p>This multi-omics study provides unprecedented insights into the transcriptional and epigenetic heterogeneity of t(8;21) AML, providing a potential actionable tool for clinical risk stratification.</p>

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A multi-omic single-cell landscape reveals transcription and epigenetic regulatory features of t(8;21) AML

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月24日

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  • Xue-Ping Li,
  • Yan Gao,
  • Bai-Tian Zhao,
  • Yu-Ting Dai,
  • Jia-Ying Mao,
  • Yang Liang,
  • Lu Jiang

摘要

Background

Comprehensive analysis of single-cell transcriptome and chromatin accessibility will contribute to interpret the heterogeneity of acute myeloid leukemia (AML). We hypothesize that integrating single-cell transcriptomic and chromatin accessibility landscapes underlying t(8;21) AML will provide valuable insights into its heterogeneous cellular properties and gene regulatory programs.

Methods

Here, we conducted paired single-cell RNA-sequencing (scRNA-seq) and single-cell ATAC sequencing on bone marrow samples from newly diagnosed t(8;21) AML patients and healthy controls. Genetic signatures extracted from scRNA-seq were built and validated across three independent cohorts (German AMLCG1999, GSE106291 and TCGA LAML).

Results

We identified TCF12, a core component of AML1-ETO-containing transcription factor complex (AETFC), as the most active transcription factor in blast cells, driving a universally repressed chromatin state. Furthermore, we delineated two functionally distinct T cell subsets, revealing that EOMES-mediated transcriptional regulation promotes the expansion of a cytotoxic T cell population (T cells_2; high GNLY, NKG7 and GZMB expression), with an increased clonality and a tendency for drug resistance. In addition, we discovered a novel leukemic CMP-like cluster characterized by high TPSAB1, HPGD and FCER1A expression. Leveraging machine learning-based integration of multi-omic profiles, we identified a robust 9-gene prognostic signature, which demonstrated significant predictive value for AML outcomes across three independent cohorts.

Conclusions

This multi-omics study provides unprecedented insights into the transcriptional and epigenetic heterogeneity of t(8;21) AML, providing a potential actionable tool for clinical risk stratification.