目的:本研究旨在阐明B细胞淋巴瘤7蛋白家族成员A(BCL7A)在急性髓系白血病(AML)中的生物学作用和调控机制。特别是其与聚嘧啶束结合蛋白1(PTBP1)的相互作用以及对癌症进展和耐药性的影响。
方法:在AML组织和细胞系中分析BCL7A的表达水平,重点关注与启动子超甲基化的关联。在体外和体内检查了与PTBP1的相互作用以及BCL7A差异表达的影响。对细胞增殖的影响,周期进展,凋亡,并进行了分化研究。此外,评估了BCL7A对干扰素调节因子7(IRF7)和3-羟基-3-甲基戊二酰辅酶A合酶1(HMGCS1)的调节作用.
结果:BCL7A在AML中由于启动子高甲基化而下调,并被PTBP1负调控。BCL7A上调阻碍AML细胞生长,诱导细胞凋亡,促进细胞分化,减少了细胞向淋巴结的浸润,提高小鼠模型的存活率。BCL7A的过表达上调IRF7和下调HMGCS1,与降低AML细胞恶性程度和降低对阿糖胞苷的抗性有关。
结论:BCL7A作为AML的肿瘤抑制因子,通过IRF7/HMGCS1途径抑制恶性进展并增强药物敏感性。这些发现提示了改善AML治疗结果的潜在治疗靶点。
OBJECTIVE: This study aimed to elucidate the biological roles and regulatory mechanisms of B-cell lymphoma 7 protein family member A (BCL7A) in acute myeloid leukemia (AML), particularly its interaction with polypyrimidine tract binding protein 1 (PTBP1) and the effects on cancer progression and drug resistance.
METHODS: BCL7A expression levels were analyzed in AML tissues and cell lines, focusing on associations with promoter hypermethylation. Interaction with PTBP1 and effects of differential expression of BCL7A were examined in vitro and in vivo. The impacts on cell proliferation, cycle progression, apoptosis, and differentiation were studied. Additionally, the regulatory roles of BCL7A on interferon regulatory factor 7 (IRF7) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) were assessed.
RESULTS: BCL7A was downregulated in AML due to promoter hypermethylation and negatively regulated by PTBP1. Upregulation of BCL7A impeded AML cell growth, induced apoptosis, promoted cell differentiation, and decreased cell infiltration into lymph nodes, enhancing survival in mouse models. Overexpression of BCL7A upregulated IRF7 and downregulated HMGCS1, linking to reduced AML cell malignancy and decreased resistance to cytarabine.
CONCLUSIONS: BCL7A acts as a tumor suppressor in AML, inhibiting malignant progression and enhancing drug sensitivity through the IRF7/HMGCS1 pathway. These findings suggest potential therapeutic targets for improving AML treatment outcomes.