Center of Biological Therapy, Southwest Hospital, Army Medical University, Chongqing, China.
Center for Precision Medicine of Cancer, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, China.
Stem Cell Res Ther. 2021 Jan 25;12(1):86. doi: 10.1186/s13287-021-02155-6.
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.
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.
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.
Our findings suggest that CD9 is a new biomarker of AML LSCs and is a promising therapeutic target.
白血病干细胞（LSCs）负责急性髓系白血病（AML）的起始、进展和复发。因此，靶向 LSCs 的治疗策略是根除 AML 的潜在方法。在这项研究中，我们旨在鉴定 LSC 特异性表面标志物，并揭示 AML LSCs 的潜在机制。
使用微阵列基因表达数据来研究候选的 AML-LSC 特异性标志物。通过流式细胞术（FC）评估 AML 细胞系、AML 患者和正常供体中的 CD9 表达。通过体外增殖、化疗药物耐药性、迁移和体内异种移植实验分析 CD9 阳性（CD9+）细胞的生物学特性。通过基因表达谱分析研究涉及 CD9 细胞功能的分子机制。分析α-2-巨球蛋白（A2M）对 CD9 细胞增殖、耐药性和迁移的影响。
CD9 是一种细胞表面蛋白，特异性表达于 AML LSCs 上，但在正常造血干细胞（HSCs）上几乎检测不到。CD9 细胞对化疗药物的耐药性更高，迁移潜力更强，与 CD9-细胞相比。更重要的是，CD9 细胞具有在免疫缺陷小鼠中重建人 AML 并促进白血病生长的能力，这表明 CD9 细胞定义了 LSC 群体。此外，我们发现 A2M 在维持 CD9 LSC 干性方面发挥着关键作用。敲低 A2M 会损害 CD9 细胞的耐药性和迁移能力。
我们的研究结果表明 CD9 是 AML LSCs 的一个新的生物标志物，是一个很有前途的治疗靶点。
