Zhou Bi, Fang Fang, Zhang YongPing, Li ZhiHeng, Hu YiXin, Li Yan, Jiao WanYan, Wu YuMeng, Wan XiaoMei, Yang Ying, Zhang FenLi, Xu Ling, Ji TongTing, Pan Jian, Hu ShaoYan
Children's Hospital of Soochow University, Suzhou, 215003, China.
Dept. of Pediatric, Suzhou Hospital of AnHui Medical University, Suzhou, 234000, China.
Int J Biol Sci. 2025 Feb 18;21(5):1966-1983. doi: 10.7150/ijbs.103211. eCollection 2025.
Leukemia is characterized by multiple rearrangements of signal transduction genes and overexpression of nonmutated genes, such as transcription factors (TFs) genes. Super-enhancers (SEs) are prevalent in human cancers and are associated with the accumulation of numerous core TFs. SEs drive the expression of core TF genes by delivering robust transcriptional activation signals. Additionally, core TFs sustain the stability and activity of SEs through mutual auto-regulation loops, creating a positive feedback loop known as the Core Transcriptional Regulation Circuit (CRC). Using ChIP-seq data, we identified the involvement of the SE-related gene ZNF217 in acute myeloid leukemia (AML), in which its functional role and underlying mechanism remain unclear. We demonstrated that ZNF217, ELF1, MEF2D, RUNX2, and FOXP1 are likely integral components of the AML CRC through various experimental techniques, including CUT&Tag, short hairpin RNA (shRNA) transduction, and Luciferase reporter assays. Notably, ZNF217 was determined to be indispensable for the proliferation and viability of AML cells both and . Subsequent analysis of RNA-seq and CUT&Tag results identified MYB as a key direct target of ZNF217. Overall, our research highlights ZNF217 as a critical oncogene in AML and offers new insights into the transcriptional regulatory mechanisms at play in AML.
白血病的特征在于信号转导基因的多重重排以及非突变基因的过表达，例如转录因子（TFs）基因。超级增强子（SEs）在人类癌症中普遍存在，并与众多核心转录因子的积累有关。SEs通过传递强大的转录激活信号来驱动核心TF基因的表达。此外，核心转录因子通过相互的自调节环维持SEs的稳定性和活性，形成一个称为核心转录调控回路（CRC）的正反馈环。利用染色质免疫沉淀测序（ChIP-seq）数据，我们确定了SE相关基因ZNF217参与急性髓系白血病（AML），但其功能作用和潜在机制仍不清楚。我们通过各种实验技术，包括切割与标签（CUT&Tag）、短发夹RNA（shRNA）转导和荧光素酶报告基因测定，证明ZNF217、ELF1、MEF2D、RUNX2和FOXP1可能是AML CRC的组成部分。值得注意的是，ZNF217被确定对于AML细胞的增殖和活力在体内和体外都是不可或缺的。随后对RNA测序（RNA-seq）和CUT&Tag结果的分析确定MYB是ZNF217的关键直接靶点。总体而言，我们的研究突出了ZNF217作为AML中的关键癌基因，并为AML中发挥作用的转录调控机制提供了新的见解。
