Single-cell transcriptome analysis defines novel molecular subtypes and reveals therapeutic implications of T/myeloid mixed-phenotype acute leukemia

作者：Bin Huang, Wenjie Liu, Yuxin Du, Ping Liu, Zixing Lu, Shiyang Zhong, Xianglin Hu, Wanting Zhou, Yuzhu Shi, Renhong Huang, Xian Zhang, Jinning Shi, Chuanyang Lu, Chunling Wang, Yu Liang, Lingxiang Wu, Wei Wu, Peng Xia, Qian Sun, Liwei Zhu, Zhi Wang, Ruohan Zhang, Xinrui Lin, Sali Lv, Qianghu Wang, Sixuan Qian, Kening Li, Ming Hong · 发表于：Genome Medicine · 年份：2025 · DOI：10.1186/s13073-025-01585-8 · 被引用次数：2 · 研究领域：Acute Myeloid Leukemia Research、Acute Lymphoblastic Leukemia research、Single-cell and spatial transcriptomics

T/myeloid mixed-phenotype acute leukemia (T/My MPAL) is a malignant disease characterized by co-expression of lymphoid and myeloid features. The lack of molecular classification of T/My MPAL results in highly heterogeneity in treatment responses and clinical outcomes. Identifying molecular subtypes and developing subtype-specific treatment strategies are crucial for improving prognosis and enabling personalized therapies. We constructed a single-cell transcriptomic landscape of T/My MPAL, acute myeloid leukemia (AML), T-cell acute lymphoid leukemia (T-ALL), and normal donors by analyzing nearly 275,000 cells. Malignant cells were identified using lineage-specific markers and healthy reference datasets. By comparing the whole transcriptomic profiles of T/My MPAL malignant cells with those of AML and T-ALL, we defined three distinct subpopulations and uncovered both intra- and inter-tumoral heterogeneity. Subpopulation-specific molecular markers were identified and validated using immunohistochemistry and independent datasets. These markers were further linked to clinical outcomes. Finally, potential subpopulation-specific therapeutic drugs were identified by correlating gene signatures with IC 50 values. Malignant cells in T/My MPAL display distinct lineage characteristics and experience differentiation arrest at a more primitive stage compared to other leukemias. Biphenotypic and bilineal MPAL subtypes defined by flow cytometry exhibit similar transcriptomic profiles, indicat...