HSCs/MPPs as cells of origin with altered differentiation hierarchy impairing immunomicroenvironment in <i>PML::RARA</i> and <i>CBFα/β</i> fusion AML
Abstract
The theoretical possibility for leukemia stem cells (LSCs) to produce both leukemia blasts and dysfunctional immune cells remains underexplored. Here, we investigate three major fusion transcription factor (fTF)-driven acute myeloid leukemia (AML) subtypes [ RUNX1(CBFα)::RUNX1T1 , PML::RARA , and CBFB::MYH11 ] using two optimized single-cell RNA-sequencing technologies to trace fTF expression in 24 de novo AML patients. We demonstrate that the fTFs are widely expressed not only in leukemia blasts but also in differentiated myeloid and lymphoid cells, indicating hematopoietic stem cells or multipotent progenitors (HSCs/MPPs) as LSCs that propagate altered cellular differentiation hierarchies, including immune cells. DNA-FISH confirms the presence of fTFs in T lymphoid and erythroid cells, and targeted sequencing of secondary mutations in sublineages of cells corroborates hierarchical and stepwise leukemogenesis. By tracking RUNX1::RUNX1T1 -expressing cells in patients with or without relapse post–frontline chemotherapy, we highlight the necessity of eradicating LSCs to achieve sustained long-term complete remission and restore a functional immune system capable of suppressing residual disease over time. Comparative single-cell transcriptome analyses further reveal that fTFs are associated with AML subtype-specific differentiation defects in both innate and adaptive immune compartments, suggesting an altered landscape of immune cell–cell communication networks that may facilitate the survival and proliferation of leukemic blasts. Through the examination of intercellular communications among various putative fTF + and normal cell populations, we developed a ligand–receptor (L–R)-based risk-scoring model with independent prognostic value. Collectively, these findings provide insights into the cells of origin of LSCs and the implications of fTF expression for the immune landscape of AML.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Niu Qiao
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Zi-Xuan Wang
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yu-Liang Zhang
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Liu-Qing-Qing Zhang
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Hong-Ming Zhu
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xiang-Qin Weng
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yong-Mei Zhu
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Wen-Yan Cheng
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jian-Feng Li
Xiamen University , , ,
Lu Jiang
School of Flexible Electronics (Future Technologies), Key Laboratory of Flexible Electronics, and Institute of Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, P. R. China
Xiao-Yu Yan
State Key Laboratory of Quantum Functional Materials, Department of Physics, and Guangdong Basic Research Center of Excellence for Quantum Science, Southern University of Science and Technology
Guang Yang
Yang Shen
Beijing National Laboratory for Condensed Matter Physics, Institute of Physics
Sheng-Yue Wang
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Zhu Chen
Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Department of Cardiology, Zhongnan Hospital
Xiao-Jian Sun
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Feng Liu
Sai-Juan Chen
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Centre for Translational Medicine at Shanghai, Research Unit of Hematologic Malignancies Genomics and Translational Research of Chinese Academy of Medical Sciences, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine