Journal
STEM CELL RESEARCH & THERAPY
Volume 12, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13287-021-02155-6
Keywords
Acute myeloid leukemia (AML); Leukemia stem cells (LSCs); CD9; Alpha-2-macroglobulin (A2M); Biomarker
Funding
- National Natural Science Foundation of China [81572464, 81602590]
- Fundamental Research Funds for the Central Universities [2020CDJQY-A071, 2019CDYGZD008]
- National Key Research and Development Program [2016YFC1303405]
- National Science Foundation of Chongqing [cstc2016shms-ztzx10006]
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CD9 has been identified as a new biomarker for AML LSCs, showing promise as a therapeutic target. CD9(+) cells exhibit higher resistance to chemotherapy drugs and migration potential, with the ability to reconstitute human AML and promote leukemia growth. Additionally, A2M plays a crucial role in maintaining CD9(+) LSC stemness, as knocking down A2M impairs drug resistance and migration of CD9(+) cells.
BackgroundLeukemia 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.MethodsMicroarray 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.ResultsCD9, 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.ConclusionOur findings suggest that CD9 is a new biomarker of AML LSCs and is a promising therapeutic target.
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