Zhang Fenli, Li Zhiheng, Fang Fang, Hu Yixin, He Zhixu, Tao Yanfang, Li Yizhen, Zhang Zimu, Zhou Bi, Yang Ying, Wu Yumeng, Wu Yijun, Wei Zhongling, Guo Ailian, Xu Ling, Zhang Yongping, Li Xiaolu, Li Yan, Yang Chunxia, Zhou Man, Pan Jian, Hu Shaoyan, Yang Xiaoyan
Department of Pediatrics, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, 550000, Guizhou, China.
Institute of Pediatric Research, Children's Hospital of Soochow University, No.92 Zhongnan Street, SIP, Suzhou, 215003, China.
Exp Hematol Oncol. 2025 Mar 1;14(1):25. doi: 10.1186/s40164-025-00612-z.
Acute myeloid leukemia (AML) is a prevalent malignancy of the hematologic system. Despite advancements in therapeutic approaches, significant heterogeneity and therapeutic resistance pose substantial challenges to treatment. Tumors driven by core transcription factors through super-enhancers can establish core transcriptional regulatory circuits (CRCs) that modulate oncogene expression programs. Identifying CRC is crucial for understanding disease-related transcriptional regulation. This study sought to predict and establish a CRC model for AML, identify genes critical for AML survival and explore their regulatory mechanisms in AML progression.
The dbCoRC tool was used for predictive analysis of H3K27ac ChIP-seq data from 11 AML samples to construct and validate the CRC model in AML patients. To elucidate the functional role of the CRC member IRF1, we utilized short hairpin RNA (shRNA) to knock down IRF1 in AML cells. RNA-seq, CUT&Tag and lipidomics technologies were subsequently used to investigate the regulatory roles and downstream mechanisms of IRF1 in AML.
This study established a core transcriptional regulatory circuit consisting of IRF1, ELF1, ETV6, RUNX2, and MEF2D, which formed an interconnected autoregulatory loop. Further investigations revealed up-regulated expression of IRF1 in AML patients, which was associated with poor prognosis. Inhibition of IRF1 expression resulted in decreased AML cell proliferation and induced apoptosis, indicating its essential role in the survival of AML cells. Additionally, this study revealed that IRF1 directly regulates the transcription of key genes such as FASN, SCD, and SREBF1 for lipid synthesis, thereby affecting lipid metabolism in AML cells.
In summary, this study identified IRF1 as a novel core transcription factor involved in AML pathogenesis. IRF1 collaborates with ELF1, ETV6, RUNX2, and MEF2D to form a core transcriptional regulatory circuit that promotes AML progression. Furthermore, we demonstrated that IRF1 directly regulates the expression of key genes involved in lipid metabolism, influencing the synthesis of diverse lipid molecules crucial for AML survival.
急性髓系白血病（AML）是血液系统中一种常见的恶性肿瘤。尽管治疗方法有所进步，但显著的异质性和治疗抗性给治疗带来了巨大挑战。由核心转录因子通过超级增强子驱动的肿瘤可以建立核心转录调控回路（CRC），从而调节癌基因表达程序。识别CRC对于理解疾病相关的转录调控至关重要。本研究旨在预测并建立AML的CRC模型，识别对AML存活至关重要的基因，并探索它们在AML进展中的调控机制。
使用dbCoRC工具对11例AML样本的H3K27ac ChIP-seq数据进行预测分析，以构建并验证AML患者的CRC模型。为了阐明CRC成员IRF1的功能作用，我们利用短发夹RNA（shRNA）在AML细胞中敲低IRF1。随后使用RNA测序、CUT&Tag和脂质组学技术研究IRF1在AML中的调控作用和下游机制。
本研究建立了一个由IRF1、ELF1、ETV6、RUNX2和MEF2D组成的核心转录调控回路，该回路形成了一个相互连接的自调控环。进一步研究发现，AML患者中IRF1表达上调，这与预后不良相关。抑制IRF1表达导致AML细胞增殖减少并诱导凋亡，表明其在AML细胞存活中起关键作用。此外，本研究表明，IRF1直接调节FASN、SCD和SREBF1等脂质合成关键基因的转录，从而影响AML细胞中的脂质代谢。
总之，本研究确定IRF1是参与AML发病机制的一种新型核心转录因子。IRF1与ELF1、ETV6、RUNX2和MEF2D协作形成一个促进AML进展的核心转录调控回路。此外，我们证明IRF1直接调节参与脂质代谢的关键基因的表达，影响对AML存活至关重要的多种脂质分子的合成。
