Lomovskaya Y V, Krasnov K S, Kobyakova M I, Kolotova A A, Ermakov A M, Senotov A S, Fadeeva I S, Fetisova E I, Lomovsky A I, Zvyagina A I, Akatov V S, Fadeev R S
Institute of Theoretical and Experimental Biophysics of the Russian Academy of Sciences, Pushchino, Moscow region, 142290 Russian Federation.
Institute of Clinical and Experimental Lymphology, Branch of the Institute of Cytology and Genetics SB RAS, Novosibirsk, 630060 Russian Federation.
Acta Naturae. 2024 Jan-Mar;16(1):48-58. doi: 10.32607/actanaturae.27317.
Acute myeloid leukemia (AML) is a malignant neoplasm characterized by extremely low curability and survival. The inflammatory microenvironment and maturation (differentiation) of AML cells induced by it contribute to the evasion of these cells from effectors of antitumor immunity. One of the key molecular effectors of immune surveillance, the cytokine TRAIL, is considered a promising platform for developing selective anticancer drugs. Previously, under conditions of the inflammatory microenvironment (a three-dimensional high-density culture of THP-1 AML cells), we demonstrated the emergence of differentiated macrophage-like THP-1ad clones resistant to TRAIL-induced death. In the present study, constitutive activation of proinflammatory signaling pathways, associated transcription factors, and increased expression of the anti-apoptotic gene were observed in TRAIL-resistant macrophage-like THP-1ad AML cells. For the first time, a bioinformatic analysis of the transcriptome revealed the main regulator, the gene, which triggers proinflammatory activation and induces resistance to TRAIL in THP-1ad macrophage-like cells.
急性髓系白血病（AML）是一种恶性肿瘤，其治愈率和生存率极低。由其诱导的AML细胞的炎症微环境和成熟（分化）有助于这些细胞逃避抗肿瘤免疫效应器。免疫监视的关键分子效应器之一，细胞因子TRAIL，被认为是开发选择性抗癌药物的一个有前景的平台。此前，在炎症微环境条件下（THP-1 AML细胞的三维高密度培养），我们证明了对TRAIL诱导的死亡具有抗性的分化型巨噬细胞样THP-1ad克隆的出现。在本研究中，在对TRAIL抗性的巨噬细胞样THP-1ad AML细胞中观察到促炎信号通路、相关转录因子的组成性激活以及抗凋亡基因表达的增加。首次通过转录组的生物信息学分析揭示了触发促炎激活并诱导THP-1ad巨噬细胞样细胞对TRAIL抗性的主要调节因子——基因。
