IDH2突变在体内通过增强S100a8/a9和NFκB信号加速TPO诱导的骨髓纤维化

EJHaem Pub Date : 2024-07-28 DOI:10.1002/jha2.983
Chien-Chin Lin, Chi-Yuan Yao, Yu-Hung Wang, Yueh-Chwen Hsu, Chang-Tsu Yuan, Tsung-Chih Chen, Chia-Lang Hsu, Sze-Hwei Lee, Jhih-Yi Lee, Pin-Tsen Shih, Chein-Jun Kao, Po-Han Chuang, Yuan-Yeh Kuo, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien
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引用次数: 0

摘要

本研究旨在利用Idh2R172K转基因小鼠,通过转录组学和分子技术阐明IDH2突变在骨髓纤维化的发生和发展中的作用。我们发现,与TPO过表达的野生Idh2(WT + TPO)小鼠相比,血栓生成素(TPO)过表达的Idh2R172K(Idh2R172K + TPO)小鼠加速了MF的进展,表现出多种炎症通路的激活,其中核因子κB(NFκB)的激活最为显著。早期中耳炎骨髓细胞的单细胞转录组显示,在WT + TPO小鼠中,S100a8/a9的表达主要局限于中性粒细胞祖细胞,但在多种类型的骨髓前体细胞中高度表达,包括Idh2R172K + TPO组的巨核细胞祖细胞。此外,与WT小鼠相比,18个月大的Idh2R172K小鼠脾脏更大,S100a8/a9-Tlr4表达增加,血清S100a8/a9水平升高。总之,我们的研究结果表明,IDH2突变会诱发促炎作用,从而进一步加剧中耳炎,Idh2R172K + TPO小鼠的S100a8/a9水平升高和NFκB过度激活就是证明。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

IDH2 mutation accelerates TPO-induced myelofibrosis with enhanced S100a8/a9 and NFκB signaling in vivo

IDH2 mutation accelerates TPO-induced myelofibrosis with enhanced S100a8/a9 and NFκB signaling in vivo

Introduction

IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear.

Methods

In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2R172K transgenic mice.

Results

We found that thrombopoietin (TPO)-overexpressed Idh2R172K (Idh2R172K + TPO) mice had accelerated progression to MF, compared with TPO-overexpressed Idh2-wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single-cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2R172K + TPO group. Furthermore, Idh2R172K mice at age of 18 months had larger spleens, increased S100a8/a9-Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations.

Conclusion

Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2R172K + TPO mice.

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