All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia.,Cell Death & Disease

当前位置： X-MOL 学术 › Cell Death Dis. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-12-10 , DOI: 10.1038/s41419-019-2172-2
Chi Huu Nguyen _{1,

2} , Katharina Bauer _{1,

2} , Hubert Hackl ₃ , Angela Schlerka _{1,

2} , Elisabeth Koller ₄ , Anastasiya Hladik ₅ , Dagmar Stoiber _{6,

7} , Johannes Zuber ₈ , Philipp B Staber ₉ , Andrea Hoelbl-Kovacic ₁₀ , Louise E Purton ₁₁ , Florian Grebien _{6,

12} , Rotraud Wieser _{1,

2}

Affiliation

Division of Oncology, Clinic of Medicine I, Medical University of Vienna, Vienna, Austria.
Comprehensive Cancer Center, Vienna, Austria.
Division of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Medical Department for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria.
Research Laboratory of Infection Biology, Clinic of Medicine I, Medical University of Vienna, Vienna, Austria.
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Institute of Molecular Pathology, Vienna, Austria.
Division of Hematology and Hemostaseology, Clinic of Medicine I, Medical University of Vienna, Vienna, Austria.
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria.
Stem Cell Regulation Unit, St. Vincent's Institute of Medical Research and Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia.
Institute of Medical Biochemistry, University of Veterinary Medicine, Vienna, Austria.

Ecotropic virus integration site 1 (EVI1), whose overexpression characterizes a particularly aggressive subtype of acute myeloid leukemia (AML), enhanced anti-leukemic activities of all-trans retinoic acid (atRA) in cell lines and patient samples. However, the drivers of leukemia formation, therapy resistance, and relapse are leukemic stem cells (LSCs), whose properties were hardly reflected in these experimental setups. The present study was designed to address the effects of, and interactions between, EVI1 and retinoids in AML LSCs. We report that Evi1 reduced the maturation of leukemic cells and promoted the abundance, quiescence, and activity of LSCs in an MLL-AF9-driven mouse model of AML. atRA further augmented these effects in an Evi1 dependent manner. EVI1 also strongly enhanced atRA regulated gene transcription in LSC enriched cells. One of their jointly regulated targets, Notch4, was an important mediator of their effects on leukemic stemness. In vitro exposure of leukemic cells to a pan-RAR antagonist caused effects opposite to those of atRA. In vivo antagonist treatment delayed leukemogenesis and reduced LSC abundance, quiescence, and activity in Evi1high AML. Key results were confirmed in human myeloid cell lines retaining some stem cell characteristics as well as in primary human AML samples. In summary, our study is the first to report the importance of EVI1 for key properties of AML LSCs. Furthermore, it shows that atRA enhances, and a pan-RAR antagonist counteracts, the effects of EVI1 on AML stemness, thus raising the possibility of using RAR antagonists in the therapy of EVI1high AML.

中文翻译：

全反式维甲酸可增强EVI1在急性髓细胞性白血病中的干细胞促进活性，而pan-RAR拮抗剂则可抵消该作用。

嗜生性病毒整合位点1（EVI1）的过表达表现出急性髓性白血病（AML）的一种特别具有侵略性的亚型，它增强了细胞系和患者样品中全反式维甲酸（atRA）的抗白血病活性。但是，白血病形成，治疗抗性和复发的驱动因素是白血病干细胞（LSC），其特性在这些实验设置中几乎没有得到体现。本研究旨在解决AML LSC中EVI1和类维生素A的作用及其之间的相互作用。我们报告说，Evi1减少白血病细胞的成熟，并促进了MLL-AF9驱动的AML小鼠模型中LSC的丰度，静止和活性。atRA以Evi1依赖的方式进一步增强了这些效果。在富含LSC的细胞中，EVI1还极大地增强了atRA调控的基因转录。他们共同调控的靶标之一，Notch4，是其对白血病干性影响的重要调节剂。白血病细胞在体外暴露于泛RAR拮抗剂引起的作用与atRA相反。体内拮抗剂治疗延缓了白血病的发生，并降低了Evi1high AML中的LSC丰度，静止性和活性。在保留了某些干细胞特征的人骨髓细胞系以及原代人AML样品中证实了关键结果。总之，我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了将RAR拮抗剂用于治疗EVI1high AML的可能性。是它们对白血病干性影响的重要介体。白血病细胞在体外暴露于泛RAR拮抗剂引起的作用与atRA相反。体内拮抗剂治疗延缓了白血病的发生，并降低了Evi1high AML中的LSC丰度，静止性和活性。在保留了某些干细胞特征的人骨髓细胞系以及原代人AML样品中证实了关键结果。总之，我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了将RAR拮抗剂用于EVI1high AML治疗的可能性。是它们对白血病干性影响的重要介体。白血病细胞在体外暴露于泛RAR拮抗剂引起的作用与atRA相反。体内拮抗剂治疗延缓了白血病的发生，并降低了Evi1high AML中的LSC丰度，静止性和活性。在保留了某些干细胞特征的人骨髓细胞系以及原代人AML样品中证实了关键结果。总之，我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了将RAR拮抗剂用于治疗EVI1high AML的可能性。体内拮抗剂治疗延缓了白血病的发生，并降低了Evi1high AML中的LSC丰度，静止性和活性。在保留了某些干细胞特征的人骨髓细胞系以及原代人AML样品中证实了关键结果。总之，我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了将RAR拮抗剂用于治疗EVI1high AML的可能性。体内拮抗剂治疗延缓了白血病的发生，并降低了Evi1high AML中的LSC丰度，静止性和活性。在保留了某些干细胞特征的人骨髓细胞系以及原代人AML样品中证实了关键结果。总之，我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了在EVI1high AML治疗中使用RAR拮抗剂的可能性。我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了将RAR拮抗剂用于治疗EVI1high AML的可能性。我们的研究是第一个报告EVI1对于AML LSC关键属性的重要性的研究。此外，它表明atRA增强了EVI1对AML干细胞的作用，并且泛RAR拮抗剂抵消了EVI1对AML干细胞的作用，从而增加了将RAR拮抗剂用于治疗EVI1high AML的可能性。

更新日期：2019-12-11

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11