Single cell multi-omics enables high-resolution identification and functional purification of human acute myeloid leukemia stem cells

作者：Asiri Ediriwickrema, Yusuke Nakauchi, Thomas Köhnke, Amy C. Fan, Xiaoyi Hu, Brooks A. Benard, Daiki Karigane, Miles H. Linde, Aaron M. Newman, Andrew J. Gentles, Ravindra Majeti · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.12.737989 · 研究领域：Acute Myeloid Leukemia Research、Single-cell and spatial transcriptomics、Chronic Myeloid Leukemia Treatments

In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML. Key Points: co-expression (hrLSC2) defines a prognostic gene signature in de novo acute myeloid leukemia. hrLSC2 marks an AML subpopulation (iLSCs) with a distinct immunophenotype.iLSCs can be purified using flow cytometry and are significantly enriched for LSCs.