circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression
circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression
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circMYBL2 是一种来自 MYBL2 的 circRNA，通过招募 PTBP1 来调节 FLT3 翻译，从而促进 FLT3-ITD AML 进展。
DOI：
10.1182/blood.2019000802
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发表时间：
2019-10-31
期刊：
影响因子：
20.3
通讯作者：
Chen, Yue-Qin
中科院分区：
文献类型：
--
作者：
Sun, Yu-Meng;Wang, Wen-Tao;Chen, Yue-Qin
FMS 样酪氨酸激酶 3 (FLT3) 内的内部串联重复 (ITD) 突变发生在高达 30% 的急性髓系白血病 (AML) 患者中，并且预后非常差。 FLT3的致癌形式是一个重要的治疗靶点，专门针对FLT3激酶的抑制剂可以诱导完全缓解；然而，由于 FLT3 二次突变的获得性耐药，已经观察到缓解后复发，这突出表明需要针对 FLT3-ITD 突变的新策略。最近的研究报道，环状RNA（circRNA）的异常形成是生物肿瘤发生相关机制和潜在的治疗靶点。在此，我们发现了一种源自细胞周期检查点基因MYBL2的circRNA circMYBL2。CircMYBL2在有FLT3-ITD突变的AML患者中比在没有FLT3-ITD突变的AML患者中表达更高。我们发现circMYBL2敲低在体外和体内特异性抑制FLT3-ITD AML细胞的增殖并促进其分化。有趣的是，我们发现circMYBL2显着影响突变型FLT3激酶的蛋白水平，从而有助于激活FLT3-ITD依赖性信号通路。从机制上讲，circMYBL2 通过增加 PTBP1 与 FLT3 mRNA 的结合来增强 FLT3 激酶的翻译效率。此外，circMYBL2敲低损害了抑制剂抗性FLT3-ITD阳性细胞的细胞活性，FLT3激酶表达显着下降，随后其下游通路失活。总之，我们首次揭示了一种特异性影响FLT3-ITD AML并通过翻译调控调节FLT3激酶水平的circRNA，表明circMYBL2可能是F LT3-ITD AML的潜在治疗靶点。
Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase-3 (FLT3) occur in up to 30% of acute myeloid leukemia (AML) patients and confer a very poor prognosis. The oncogenic form of FLT3 is an important therapeutic target, and inhibitors specifically targeting FLT3 kinase can induce complete remission; however, relapse after remission has been observed due to acquired resistance with secondary mutations in FLT3, highlighting the need for new strategies to target FLT3-ITD mutations. Recent studies have reported that the aberrant formations of circular RNAs (circRNAs) are biological tumorigenesis-relevant mechanisms and potential therapeutic targets. Herein, we discovered a circRNA, circMYBL2, derived from the cell cycle checkpoint gene MYBL2 CircMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of PTBP1 to FLT3 mRNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD-positive cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for F LT3-ITD AML.