Li Xue-Ping, Gao Yan, Zhao Bai-Tian, Dai Yu-Ting, Mao Jia-Ying, Liang Yang, Jiang Lu
Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
J Transl Med. 2025 Jul 24;23(1):816. doi: 10.1186/s12967-025-06659-0.
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.
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).
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.
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.
对单细胞转录组和染色质可及性进行综合分析将有助于解释急性髓系白血病（AML）的异质性。我们假设，整合t(8;21) AML潜在的单细胞转录组和染色质可及性图谱，将为其异质性细胞特性和基因调控程序提供有价值的见解。
在此，我们对新诊断的t(8;21) AML患者和健康对照的骨髓样本进行了配对单细胞RNA测序（scRNA-seq）和单细胞ATAC测序。从scRNA-seq中提取的基因特征在三个独立队列（德国AMLCG1999、GSE106291和TCGA LAML）中构建并验证。
我们确定了含AML1-ETO转录因子复合物（AETFC）的核心成分TCF12是母细胞中最活跃的转录因子，驱动普遍抑制的染色质状态。此外，我们描绘了两个功能不同的T细胞亚群，揭示EOMES介导的转录调控促进了细胞毒性T细胞群体（T细胞_2；高GNLY、NKG7和GZMB表达）的扩增，克隆性增加且有耐药倾向。此外，我们发现了一个以高TPSABi、HPGD和FCER1A表达为特征的新型白血病CMP样簇。利用基于机器学习的多组学图谱整合，我们确定了一个强大的9基因预后特征，该特征在三个独立队列中对AML预后具有显著的预测价值。
这项多组学研究为t(8;21) AML的转录和表观遗传异质性提供了前所未有的见解，为临床风险分层提供了一个潜在的可操作工具。
