癌基因FLT3内部串联复制（FLT3-ITD）突变占急性髓性白血病（AML）病例的30％，并诱发细胞转化。以前，我们发现E2F转录因子1（E2F1）参与AML细胞分化。在这里，我们报告AML患者中E2F1表达异常上调，尤其是携带FLT3-ITD的AML患者。 E2F1敲下抑制培养FLT3-ITD阳性AML细胞的增殖并增加细胞对化疗的敏感性。 E2F1缺乏的FLT3-ITD + AML细胞通过减少的白血病负荷和在接受异种移植的NOD-PrkdcscidIl2rgem1/Smoc小鼠中的延长生存时间失去了其恶性表现。此外，E2F1敲下可拮抗FLT3-ITD驱动的人类CD34 +造血干细胞和祖细胞的转化。从机制上看，FLT3-ITD增强了AML细胞中E2F1的表达和核累积。进一步使用染色质免疫共沉淀测序和代谢组分析表明，人工FLT3-ITD促进了编码嘌呤代谢的关键酶调节因子的基因上E2F1的招募，并支持AML细胞增殖。综上，本研究表明，E2F1激活的嘌呤代谢是AML中FLT3-ITD的关键下游过程，也是FLT3-ITD + AML患者的潜在靶点。 版权所有©2023 Elsevier Inc.

Oncogene FLT3 internal tandem duplication (FLT3-ITD) mutation accounts for 30 % of acute myeloid leukaemia (AML) cases and induces transformation. Previously, we found that E2F transcription factor 1 (E2F1) was involved in AML cell differentiation. Here, we reported that E2F1 expression was aberrantly upregulated in AML patients, especially in AML patients carrying FLT3-ITD. E2F1 knockdown inhibited cell proliferation and increased cell sensitivity to chemotherapy in cultured FLT3-ITD-positive AML cells. E2F1-depleted FLT3-ITD+ AML cells lost their malignancy as shown by the reduced leukaemia burden and prolonged survival in NOD-PrkdcscidIl2rgem1/Smoc mice receiving xenografts. Additionally, FLT3-ITD-driven transformation of human CD34+ hematopoietic stem and progenitor cells was counteracted by E2F1 knockdown. Mechanistically, FLT3-ITD enhanced the expression and nuclear accumulation of E2F1 in AML cells. Further study using chromatin immunoprecipitation-sequencing and metabolomics analyses revealed that ectopic FLT3-ITD promoted the recruitment of E2F1 on genes encoding key enzymatic regulators of purine metabolism and thus supported AML cell proliferation. Together, this study demonstrates that E2F1-activated purine metabolism is a critical downstream process of FLT3-ITD in AML and a potential target for FLT3-ITD+ AML patients.Copyright © 2023 Elsevier Inc. All rights reserved.