剪接因子YBX1介導JAK2突變腫瘤的持久性
作者：
小柯機器人發布時間：2020/11/27 14:20:03
研究人員表示，Janus激酶（JAK）介導對造血細胞中細胞因子、激素和生長因子的響應。JAK基因JAK2在衰老的造血系統和造血系統癌症中經常發生突變。JAK2突變組成性激活下遊信號，並且是骨髓增生性腫瘤（MPN）的驅動因子。在臨床應用中，JAK抑制劑對JAK2突變克隆的總體疾病負擔具有混合效應，這促使研究人員好奇疾病持久性的機制。
通過深入的磷酸化蛋白質組分析，研究人員確定了參與mRNA加工的蛋白質為突變JAK2的目標。研究人員發現失活的YBX1（JAK2的一個翻譯後修飾靶標）使得細胞對凋亡敏感，並導致RNA錯誤剪接、內含子富集以及ERK信號轉錄調控的紊亂。
與藥理學上的JAK抑制作用相結合，YBX1失活會誘導依賴JAK2的小鼠和原代人細胞凋亡，從而導致體內惡性克隆消退，並誘導分子緩解。這鑑定並驗證了一種細胞內在機制，即：差異的蛋白質磷酸化導致JAK2-ERK信號的剪接依賴性改變和JAK2V617F惡性克隆的維持。靶向YAKX1依賴的ERK信號轉導並結合JAK2抑制可以根除具有JAK2突變的細胞。
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