文章：

OTS167阻断FLT3翻译并与FLT3抑制剂协同作用于FLT3突变型急性髓系白血病

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia

原文发布日期：2021-03-03

DOI: 10.1038/s41408-021-00433-3

类型: Article

开放获取: 是

英文摘要：

Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood. OTS167 alone or in combination with tyrosine kinase inhibitors (TKIs) were used to investigate the effect of OTS167 on FLT3 signaling and expression in human FLT3 mutant AML cell lines and primary cells. We describe a mechanism whereby OTS167 blocks FLT3 expression by blocking FLT3 translation and inhibiting phosphorylation of eukaryotic initiation factor 4E–binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4B (eIF4B). OTS167 in combination with TKIs results in synergistic induction of FLT3 mutant cell death in FLT3 mutant cell lines and prolonged survival in a FLT3 mutant AML xenograft mouse model. Our findings suggest signaling through MELK is necessary for the translation and expression of FLT3-ITD, and blocking MELK with OTS167 represents a viable therapeutic strategy for patients with FLT3 mutant AML.
 

摘要翻译： 

Fms样酪氨酸激酶3（FLT3）的内部串联重复（-ITD）突变在FLT3突变急性髓系白血病（AML）已存在的驱动突变背景下，提供生长和促生存信号。母胚亮氨酸拉链激酶（MELK）是一个异常表达的基因，已被确定为AML的治疗靶点。MELK抑制剂OTS167可诱导AML细胞（包括携带FLT3突变的细胞）死亡，但MELK的作用及OTS167的作用机制尚不明确。通过单独或联合使用酪氨酸激酶抑制剂（TKIs），研究OTS167对人源FLT3突变AML细胞系及原代细胞中FLT3信号传导和表达的影响。我们阐明了一种机制：OTS167通过阻断FLT3翻译并抑制真核起始因子4E结合蛋白1（4E-BP1）和真核翻译起始因子4B（eIF4B）的磷酸化，从而抑制FLT3表达。在FLT3突变细胞系中，OTS167联合TKIs可协同诱导FLT3突变细胞死亡，并在FLT3突变AML异种移植小鼠模型中延长生存期。我们的研究结果表明，MELK介导的信号传导对FLT3-ITD的翻译和表达至关重要，使用OTS168阻断MELK为FLT3突变AML患者提供了一种可行的治疗策略。

原文链接：

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia