Wang Li-Na, Tang Yan-Lai, Zhang Yin-Chuan, Zhang Zu-Han, Liu Xiao-Jian, Ke Zhi-Yong, Li Yu, Tan Hui-Zhen, Huang Li-Bin, Luo Xue-Qun
a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
Leuk Lymphoma. 2017 Oct;58(10):2426-2438. doi: 10.1080/10428194.2017.1289522. Epub 2017 Mar 9.
FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.
FLT3内部串联重复突变（FLT3-ITD）约在30%的急性髓系白血病（AML）中出现，并与不良预后相关。目前可用的FLT3抑制剂在体外对FLT3-ITD AML具有活性，但临床活性有限。报告显示，三氧化二砷（ATO）/全反式维甲酸（ATRA）联合用药可改善急性早幼粒细胞白血病的预后，尤其是伴有FLT3-ITD的患者，且单独使用ATO或ATRA可增强经FLT3抑制剂处理的FLT3-ITD AML细胞的凋亡，这为研究ATO/ATRA在FLT3-ITD AML中的作用提供了理论依据。在此，我们证明ATO/ATRA联合用药对FLT3-ITD AML细胞系（MV4;11/MOLM-13）具有选择性协同细胞毒性。受ATO/ATRA影响的信号通路包括FLT3/STAT5/MYC、FLT3/STAT5/E2F1、FLT3/ERK/ATF5和FLT3/AKT/ATF5。ATF5可能在FLT3-ITD AML中作为癌基因发挥作用。我们的研究结果提供了实验证据，支持在体内对FLT3-ITD AML进一步探索ATO/ATRA，并值得对包含ATO/ATRA联合用药的方案进行临床评估。
