小柯机器人

剪接因子YBX1介导JAK2突变肿瘤的持久性
2020-11-27 14:20

德国格赖夫斯瓦尔德大学Florian H. Heidel、马普研究所Matthias Mann等研究人员合作发现,剪接因子YBX1介导JAK2突变肿瘤的持久性。2020年11月25日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员表示,Janus激酶(JAK)介导对造血细胞中细胞因子、激素和生长因子的响应。JAK基因JAK2在衰老的造血系统和造血系统癌症中经常发生突变。JAK2突变组成性激活下游信号,并且是骨髓增生性肿瘤(MPN)的驱动因子。在临床应用中,JAK抑制剂对JAK2突变克隆的总体疾病负担具有混合效应,这促使研究人员好奇疾病持久性的机制。
 
通过深入的磷酸化蛋白质组分析,研究人员确定了参与mRNA加工的蛋白质为突变JAK2的目标。研究人员发现失活的YBX1(JAK2的一个翻译后修饰靶标)使得细胞对凋亡敏感,并导致RNA错误剪接、内含子富集以及ERK信号转录调控的紊乱。
 
与药理学上的JAK抑制作用相结合,YBX1失活会诱导依赖JAK2的小鼠和原代人细胞凋亡,从而导致体内恶性克隆消退,并诱导分子缓解。这鉴定并验证了一种细胞内在机制,即:差异的蛋白质磷酸化导致JAK2-ERK信号的剪接依赖性改变和JAK2V617F恶性克隆的维持。靶向YAKX1依赖的ERK信号转导并结合JAK2抑制可以根除具有JAK2突变的细胞。
 
附:英文原文

Title: Splicing factor YBX1 mediates persistence of JAK2 -mutated neoplasms

Author: Ashok Kumar Jayavelu, Tina M. Schnder, Florian Perner, Carolin Herzog, Arno Meiler, Gurumoorthy Krishnamoorthy, Nicolas Huber, Juliane Mohr, Brbel Edelmann-Stephan, Rebecca Austin, Sabine Brandt, Francesca Palandri, Nicolas Schrder, Berend Isermann, Frank Edlich, Amit U. Sinha, Martin Ungelenk, Christian A. Hbner, Robert Zeiser, Susann Rahmig, Claudia Waskow, Iain Coldham, Thomas Ernst, Andreas Hochhaus, Stefanie Jilg, Philipp J. Jost, Ann Mullally, Lars Bullinger, Peter R. Mertens, Steven W. Lane, Matthias Mann, Florian H. Heidel

Issue&Volume: 2020-11-25

Abstract: Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells1,2. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system3,4 and in haematopoietic cancers5. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones6,7, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2–ERK signalling and the maintenance of JAK2V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2.

DOI: 10.1038/s41586-020-2968-3

Source: https://www.nature.com/articles/s41586-020-2968-3

 

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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