Journal Article

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

Cai, Yun, Sun, Qian, Li, Ning, Qian, Sixuan, Wang, Zhi, Li, Jianyong, Li, Kening, Wu, Wei, Huang, Bin, Liu, Wenjie, Zhu, Mengyan, Li, Liangyu, Bosco, Bakwatanisa, Zhang, Lishen, Wang, Qianghu, Lv, Yan, Hong, Ming, Wu, Lingxiang, Du, Yuxin, Liu, Ping

2023

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Acute myeloid leukemia / Bone marrow / CD49d antigen / CD99 antigen / Chemoresistance / Chemotherapy / Flow cytometry / Galectin-1 / Gene sequencing / Heterogeneity / Leukemia / Monocytes / Therapeutic targets / Xenografts / Xenotransplantation