曲美替尼增强全反式维甲酸诱导的急性髓系白血病细胞分化。
Trametinib enhances ATRA-induced differentiation in AML cells.
作者信息
Lu Hao, Li Ze-Yi, Ding Ming, Liang Cui, Weng Xiang-Qin, Sheng Yan, Wu Jing, Cai Xun
机构信息
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Hematology Oncology, Central Hospital of Minhang District, Shanghai, China.
出版信息
Leuk Lymphoma. 2021 Dec;62(14):3361-3372. doi: 10.1080/10428194.2021.1961231. Epub 2021 Aug 6.
All-trans retinoic acid (ATRA) is only clinically useful in acute promyelocytic leukemia (APL), but not other subtypes of acute myeloid leukemia (AML). In the present study, a clinically achievable concentration of trametinib, a highly selective inhibitor of MEK, enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as AML primary cells. Moreover, trametinib-ATRA (tra-ATRA) co-treatment restored ATRA sensitivity in ATRA-resistant AML cell line, HL-60Res. The protein level of STAT3 and the phosphorylation of Akt or JNK were enhanced with tra-ATRA treatment in HL-60, U937, and HL-60Res cells, respectively. Furthermore, tra-ATRA-induced differentiation in HL-60, U937, and HL-60Res cells was inhibited by STAT3, PI3K, and JNK inhibitors, respectively. Therefore, STAT3, Akt, and JNK signaling pathways were involved in tra-ATRA-induced differentiation in HL-60, U937, and HL-60Res cells, respectively. Taken together, our findings may provide novel therapeutic strategies for AML patients.
全反式维甲酸（ATRA）仅在急性早幼粒细胞白血病（APL）的治疗中具有临床应用价值，而对急性髓系白血病（AML）的其他亚型无效。在本研究中，一种临床上可达到的浓度的曲美替尼（一种MEK的高选择性抑制剂）增强了ATRA对AML细胞系HL-60和U937以及AML原代细胞的诱导分化作用。此外，曲美替尼与ATRA联合治疗（tra-ATRA）恢复了ATRA耐药的AML细胞系HL-60Res对ATRA的敏感性。在HL-60、U937和HL-60Res细胞中，tra-ATRA处理分别增强了STAT3的蛋白水平以及Akt或JNK的磷酸化。此外，HL-60、U937和HL-60Res细胞中tra-ATRA诱导的分化分别被STAT3、PI3K和JNK抑制剂所抑制。因此，STAT3、Akt和JNK信号通路分别参与了tra-ATRA诱导的HL-60、U937和HL-60Res细胞的分化过程。综上所述，我们的研究结果可能为AML患者提供新的治疗策略。
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