CD9, a potential leukemia stem cell marker, regulates drug resistance and leukemia development in acute myeloid leukemia

• Main Authors: Yongliang Liu, Guiqin Wang, Jiasi Zhang, Xue Chen, Huailong Xu, Gang Heng, Jun Chen, Yongchun Zhao, Jiatao Li, Yuanli Ni, Yingzi Zhang, Juanjuan Shan, Cheng Qian
• Format: Article
• Language: English
• Published: BMC 2021-01-01
• Series: Stem Cell Research & Therapy
• Subjects: Acute myeloid leukemia (AML); Leukemia stem cells (LSCs); CD9; Alpha-2-macroglobulin (A2M); Biomarker
• Online Access: https://doi.org/10.1186/s13287-021-02155-6

Abstract Background Leukemia stem cells (LSCs) are responsible for the initiation, progression, and relapse of acute myeloid leukemia (AML). Therefore, a therapeutic strategy targeting LSCs is a potential approach to eradicate AML. In this study, we aimed to identify LSC-specific surface markers and uncover the underlying mechanism of AML LSCs. Methods Microarray gene expression data were used to investigate candidate AML-LSC-specific markers. CD9 expression in AML cell lines, patients with AML, and normal donors was evaluated by flow cytometry (FC). The biological characteristics of CD9-positive (CD9+) cells were analyzed by in vitro proliferation, chemotherapeutic drug resistance, migration, and in vivo xenotransplantation assays. The molecular mechanism involved in CD9+ cell function was investigated by gene expression profiling. The effects of alpha-2-macroglobulin (A2M) on CD9+ cells were analyzed with regard to proliferation, drug resistance, and migration. Results CD9, a cell surface protein, was specifically expressed on AML LSCs but barely detected on normal hematopoietic stem cells (HSCs). CD9+ cells exhibit more resistance to chemotherapy drugs and higher migration potential than do CD9-negative (CD9−) cells. More importantly, CD9+ cells possess the ability to reconstitute human AML in immunocompromised mice and promote leukemia growth, suggesting that CD9+ cells define the LSC population. Furthermore, we identified that A2M plays a crucial role in maintaining CD9+ LSC stemness. Knockdown of A2M impairs drug resistance and migration of CD9+ cells. Conclusion Our findings suggest that CD9 is a new biomarker of AML LSCs and is a promising therapeutic target.