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Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9.

Trib1通过调节hoxa9的转录程序促进急性髓系白血病进展。

  • 影响因子:7.27
  • DOI:10.1182/blood.2019004586
  • 作者列表:"Yoshino S","Yokoyama T","Sunami Y","Takahara T","Nakamura A","Yamazaki Y","Tsutsumi S","Aburatani H","Nakamura T
  • 发表时间:2021-01-07
Abstract

:The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance extracellular signal-regulated kinase (ERK) phosphorylation. A close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis, where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. Chromatin immunoprecipitation sequencing analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased messenger RNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPα p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

摘要

: 假激酶Trib1作为髓样癌基因,将E3泛素连接酶COP1募集到C/ebp α,并与MEK1相互作用以增强细胞外信号调节激酶 (ERK) 磷酸化。在髓系白血病发生中观察到Trib1对Hoxa9的密切遗传效应,其中Trib1过表达显著加速Hoxa9-induced白血病发作。然而,Trib1如何在功能上调节Hoxa9转录活性的机制尚不清楚。在此,我们提供了Trib1调节Hoxa9-associated超增强子的证据。染色质免疫沉淀测序分析鉴定了Erg、Spns2、Rgl1和Pik3cd基因座的超增强子处组蛋白H3K27Ac信号增加,以及这些基因的信使RNA表达增加。超增强子活性的修饰主要是通过Trib1降解C/ebp α p42实现的,其中MEK/ERK途径的贡献很小。Erg的沉默消除了Trib1过表达获得的生长优势,表明Erg是Trib1/Hoxa9轴的关键下游靶标。此外,用BRD4抑制剂JQ1治疗急性髓性白血病 (AML) 细胞在体外和体内均显示出Trib1/Erg依赖性方式的生长抑制。在人AML细胞系中也观察到TRIB1对ERG的上调,表明Trib1是Hoxa9-associated AML的潜在治疗靶标。总之,我们的研究证明了一种新的机制,即Trib1在髓系白血病发生中调节染色质和Hoxa9-driven转录。

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