Acute promyelocytic leukemia (APL) is a type of acute myeloid leukemia (AML) with a high mortality rate, and the production of PML-RARα fusion protein is the cause of its pathogenesis. Our group has synthesized a novel compound, 4-amino-2-trifluoromethyl-phenyl retinate (ATPR), by structural modification of All-trans retinoic acid (ATRA), which has strong cell differentiation-inducing effects and inhibits the expression of PML-RARα. In this study, acute promyelocytic leukemia NB4 cells before and after ATPR induction were analyzed by whole transcriptome microarray, and the expression of lncRNA CONCR was found to be significantly downregulated. The role of CONCR in ATPR-induced cell differentiation and cycle arrest was explored through overexpression and silencing of CONCR. And then the database was used to predict that CONCR may bind to DEAD/H-Box Helicase 11 (DDX11) protein to further explore the role of CONCR binding to DDX11. The results showed that ATPR could reduce the expression of CONCR, and overexpression of CONCR could reverse the ATPR-induced cell differentiation and cycle blocking effect, and conversely silencing of CONCR could promote this effect. RNA immunoprecipitation (RIP) experiments showed that CONCR could bind to DDX11, the protein expression levels of DDX11 and PML-RARα were elevated after overexpression of CONCR. These results suggest that ATPR can regulate the expression of DDX11 through CONCR to affect the expression of PML-RARα fusion protein, which in turn induces the differentiation and maturation of APL cells.

中文翻译：

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ATPR 通过 lncRNA CONCR/DDX11/PML-RARα 信号轴诱导急性早幼粒细胞白血病细胞分化和周期停滞

急性早幼粒细胞白血病（APL）是一种死亡率较高的急性髓系白血病（AML），PML-RARα融合蛋白的产生是其发病的原因。我们课题组通过全反式视黄酸（ATRA）的结构修饰，合成了一种新型化合物4-氨基-2-三氟甲基苯基视黄酸酯（ATPR），该化合物具有较强的细胞分化诱导作用，可抑制PML-的表达。 RARα。本研究通过全转录组芯片对 ATPR 诱导前后的急性早幼粒细胞白血病 NB4 细胞进行分析，发现 lncRNA CONCR 的表达显着下调。通过 CONCR 的过表达和沉默，探讨了 CONCR 在 ATPR 诱导的细胞分化和周期停滞中的作用。然后利用该数据库预测CONCR可能与DEAD/H-Box Helicase 11（DDX11）蛋白结合，进一步探讨CONCR与DDX11结合的作用。结果表明，ATPR可以降低CONCR的表达，过表达CONCR可以逆转ATPR诱导的细胞分化和周期阻断效应，反之沉默CONCR可以促进这种效应。 RNA免疫沉淀(RIP)实验表明CONCR可以与DDX11结合，过表达CONCR后DDX11和PML-RARα的蛋白表达水平升高。这些结果表明ATPR可以通过CONCR调节DDX11的表达来影响PML-RARα融合蛋白的表达，进而诱导APL细胞的分化和成熟。