Chen Jinzhu, Feng Juan, Fang Zhihong, Ye Jing, Chen Qinwei, Chen Qiuling, Chen Kai, Xiong Xiaoming, Li Guowei, Song Haihan, Xu Bing
Department of Hematology, The First Hospital of Longhai 363199 Fujian, P. R. China.
Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University Xiamen 361003, P. R. China.
Am J Transl Res. 2021 Mar 15;13(3):1494-1504. eCollection 2021.
Leukemias driven by chromosomal translocation of the mixed-lineage leukemia (MLL) gene are highly prevalent in hematological malignancy. The poor survival rate and lack of effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. The present study aimed to investigate the potential effectiveness and mechanism of Anlotinib, a novel receptor tyrosine kinase inhibitor, in MLL-r acute myeloid leukemia (AML). The findings revealed that Anlotinib significantly inhibited the growth of MLL-r AML cells in both and a murine xenograft model. RNA sequencing identified that multiple genes involved in DNA damage response were responsible for Anlotinib activity. To further elucidate the correlation between the DNA damage response induced by Anlotinib and MLL fusion, Gene Expression Profiling Interactive Analysis (GEPIA) was conducted. It revealed that Anlotinib impaired DNA damage response via inhibiting SETD1A and AKT. In conclusion, Anlotinib exerts anti-leukemia function by inhibiting SETD1A/AKT-mediated DNA damage response and highlights a novel mechanism underlying Anlotinib in the treatment of MLL-r AML.
由混合谱系白血病（MLL）基因的染色体易位驱动的白血病在血液系统恶性肿瘤中非常普遍。MLL重排（MLL-r）白血病患者的低生存率以及缺乏有效的靶向治疗方法，凸显了迫切需要增进对这些恶性肿瘤的认识并开发新的治疗方法。本研究旨在探讨新型受体酪氨酸激酶抑制剂安罗替尼在MLL-r急性髓系白血病（AML）中的潜在疗效及作用机制。研究结果显示，安罗替尼在体外和小鼠异种移植模型中均能显著抑制MLL-r AML细胞的生长。RNA测序确定，多个参与DNA损伤反应的基因与安罗替尼的活性有关。为进一步阐明安罗替尼诱导的DNA损伤反应与MLL融合之间的相关性，进行了基因表达谱交互分析（GEPIA）。结果显示，安罗替尼通过抑制SETD1A和AKT来损害DNA损伤反应。总之，安罗替尼通过抑制SETD1A/AKT介导的DNA损伤反应发挥抗白血病功能，并揭示了安罗替尼治疗MLL-r AML的一种新机制。
