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

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.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC7836575 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature