Single-cell analysis reveals the chemotherapy-induced cellular reprogramming and novel therapeutic targets in relapsed/refractory acute myeloid leukemia

被引:0
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作者
Kening Li
Yuxin Du
Yun Cai
Wenjie Liu
Yan Lv
Bin Huang
Lishen Zhang
Zhi Wang
Ping Liu
Qian Sun
Ning Li
Mengyan Zhu
Bakwatanisa Bosco
Liangyu Li
Wei Wu
Lingxiang Wu
Jianyong Li
Qianghu Wang
Ming Hong
Sixuan Qian
机构
[1] The Affiliated Cancer Hospital of Nanjing Medical University,Center for Global Health, School of Public Health
[2] Jiangsu Cancer Hospital,Department of Bioinformatics
[3] Jiangsu Institute of Cancer Research,Department of Hematology
[4] Nanjing Medical University,Department of Hematology
[5] Nanjing Medical University,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine
[6] The First Affiliated Hospital of Nanjing Medical University,Biomedical Big Data Center
[7] Jiangsu Province Hospital,undefined
[8] Key Laboratory of Hematology of Nanjing Medical University,undefined
[9] The Affiliated Wuxi No. 2 People’s Hospital of Nanjing Medical University,undefined
[10] Pukou CLL Center,undefined
[11] Nanjing Medical University,undefined
[12] Nanjing Medical University,undefined
来源
Leukemia | 2023年 / 37卷
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摘要
Chemoresistance and relapse are the leading cause of AML-related deaths. Utilizing single-cell RNA sequencing (scRNA-seq), we dissected the cellular states of bone marrow samples from primary refractory or short-term relapsed AML patients and defined the transcriptional intratumoral heterogeneity. We found that compared to proliferating stem/progenitor-like cells (PSPs), a subpopulation of quiescent stem-like cells (QSCs) were involved in the chemoresistance and poor outcomes of AML. By performing longitudinal scRNA-seq analyses, we demonstrated that PSPs were reprogrammed to obtain a QSC-like expression pattern during chemotherapy in refractory AML patients, characterized by the upregulation of CD52 and LGALS1 expression. Flow cytometric analysis further confirmed that the preexisting CD99+CD49d+CD52+Galectin-1+ (QSCs) cells at diagnosis were associated with chemoresistance, and these cells were further enriched in the residual AML cells of refractory patients. Interaction of CD52-SIGLEC10 between QSCs and monocytes may contribute to immune evading and poor outcomes. Furthermore, we identified that LGALS1 was a promising target for chemoresistant AML, and LGALS1 inhibitor could help eliminate QSCs and enhance the chemotherapy in patient-derived primary AML cells, cell lines, and AML xenograft models. Our results will facilitate a better understanding of the AML chemoresistance mechanism and the development of novel therapeutic strategies for relapsed/refractory AML patients.
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页码:308 / 325
页数:17
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