Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, China.
Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, HUST, Wuhan, China.
Theranostics. 2022 Jul 18;12(12):5537-5550. doi: 10.7150/thno.72786. eCollection 2022.
Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated . The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth , which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.
尽管维奈托克改变了急性髓系白血病（AML）和慢性淋巴细胞白血病（CLL）的治疗模式，但它在弥漫性大 B 细胞淋巴瘤（DLBCL）的治疗中效果较差。在这里，我们探讨了酰基甘油激酶（AGK）是否调节 DLBCL 对维奈托克的敏感性及其在细胞系和临床前动物模型中的机制。测定了七种 DLBCL 细胞系中 AGK 的表达和对维奈托克的敏感性。通过慢病毒在 DLBCL 细胞中敲低和过表达 AGK，评估维奈托克诱导的细胞凋亡和 PTEN-FOXO1-BCL-2 信号通路。在植入对照或稳定转导 shAGK 的 SU-DHL4 细胞的免疫缺陷 NCG 小鼠中评估维奈托克和 PTEN-FOXO1-BCL-2 信号通路的疗效。评估了 DLBCL 患者肿瘤组织中 AGK、BCL-2 和 FOXO1 的表达。AGK 表达与 DLBCL 对维奈托克的敏感性呈负相关。抑制 AGK 使 DLBCL 细胞对维奈托克更敏感。机制上，AGK 磷酸化并失活了 PTEN，导致 AKT 激活和 FOXO1 核转位减少。抑制 AGK 还增强了维奈托克抑制 DLBCL 肿瘤生长的疗效，这依赖于 FOXO1。在人类 DLBCL 肿瘤组织中，AGK 的表达与 BCL-2 的表达以及核 FOXO1 的含量呈负相关。我们的数据表明，AGK 通过 PTEN-FOXO1-BCL-2 信号通路调节 DLBCL 对维奈托克的反应。靶向 AGK 可能增强维奈托克治疗 DLBCL 患者的疗效。
