Cao MeiWan, Peng BaoLing, Xu WanFu, Chen PeiYu, Li HuiWen, Cheng Yang, Chen Huan, Ye LiPing, Xie Jing, Wang HongLi, Ren Lu, Xiong LiYa, Zhu JingNan, Xu XiangYe, Geng LanLan, Gong SiTang
Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou City, Guangdong Province, 510623, China.
Center for child health and mental health, Shenzhen Children's Hospital, Shenzhen City, Guangdong Province, China.
Mediterr J Hematol Infect Dis. 2023 Jul 1;15(1):e2023040. doi: 10.4084/MJHID.2023.040. eCollection 2023.
Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal diseases that are characterized by ineffective bone marrow hematopoiesis. Since studies have confirmed the significance of miRNAs in ineffective hematopoiesis in MDS, the current report elucidated the mechanism mediated by miR-155-5p. The bone marrow of MDS patients was collected to detect miR-155-5p and to analyze the correlation between miR-155-5p and clinicopathological variables. Isolated bone marrow CD34+ cells were transfected with lentiviral plasmids that interfere with miR-155-5p, followed by apoptosis analysis. Finally, miR-155-5p-targeted regulation of RAC1 expression was identified, as well as the interaction between RAC1 and CREB, the co-localization of RAC1 and CREB, and the binding of CREB to miR-15b. As measured, miR-155-5p was upregulated in the bone marrow of MDS patients. Further cell experiments validated that miR-155-5p promoted CD34+ cell apoptosis. miR-155-5p could reduce the transcriptional activity of miR-15b by inhibiting RAC1, dissociating the interaction between RAC1 and CREB, and inhibiting the activation of CREB. Upregulating RAC1, CREB, or miR-15b could reduce miR-155-5p-mediated apoptosis promotion on CD34+ cells. Additionally, miR-155-5p could force PD-L1 expression, and this effect was impaired by elevating RAC1, CREB, or miR-15b. In conclusion, miR-155-5p mediates PD-L1-mediated apoptosis of CD34+ cells in MDS by RAC1/CREB/miR-15b axis, thereby inhibiting bone marrow hematopoiesis.
骨髓增生异常综合征（MDS）是一组异质性髓系克隆性疾病，其特征为骨髓造血无效。由于研究已证实微小RNA（miRNA）在MDS无效造血中的重要性，本报告阐明了由miR-155-5p介导的机制。收集MDS患者的骨髓以检测miR-155-5p，并分析miR-155-5p与临床病理变量之间的相关性。用干扰miR-155-5p的慢病毒质粒转染分离出的骨髓CD34+细胞，随后进行凋亡分析。最后，确定了miR-155-5p对RAC1表达的靶向调控，以及RAC1与CREB之间的相互作用、RAC1与CREB的共定位，以及CREB与miR-15b的结合。检测发现，MDS患者骨髓中miR-155-5p上调。进一步的细胞实验证实，miR-155-5p促进CD34+细胞凋亡。miR-155-5p可通过抑制RAC1、解离RAC1与CREB之间的相互作用以及抑制CREB的激活来降低miR-15b的转录活性。上调RAC1、CREB或miR-15b可减少miR-155-5p介导的对CD34+细胞凋亡的促进作用。此外，miR-155-5p可促使程序性死亡受体配体1（PD-L1）表达，而提高RAC1、CREB或miR-15b可削弱这种作用。总之，miR-155-5p通过RAC1/CREB/miR-15b轴介导MDS中PD-L1介导的CD34+细胞凋亡，从而抑制骨髓造血。
