慢性TNF在衰老的微环境中加剧了Tet2功能丧失骨髓扩张
Candice Quin1,2,3, Erica N DeJong1,2, Amy J M McNaughton4
1Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
Blood advances
|June 26, 2024
概括
瘤亡因子 (TNF) 在衰老中驱动TET2-突变性克隆性血液形成 (CHIP) 的扩张. 向TNF可能会降低CHIP负担,为髓状瘤提供一种新的治疗策略.
科学领域:
- 血液学 血液学 血液学
- 免疫学 免疫学 免疫学
- 衰老研究研究 衰老研究
背景情况:
- 随着年龄的增长,TET2体内突变变异常见,促进不确定潜力的克隆性血液形成 (CHIP).
- CHIP增加了骨髓瘤和与年龄有关的疾病的风险.
- 驱动TET2突变CHIP扩张的外部因素尚不清楚.
研究的目的:
- 调查瘤亡因子 (TNF) 在TET2-突变性造血干细胞 (HSC) 在体内扩张中的作用.
- 为了确定与年龄相关的TNF增加是否有助于TET2突变CHIP的克隆扩张.
主要方法:
- 使用野生型 (WT) 和TNF-/-基因型生成混合骨髓模拟小鼠.
- 复制后的小鼠具有WT CD45.1+和Tet2-/- CD45.2+ HSCs.
- 在老WT和TNF-/-接受者小鼠中分析了HSC扩张和骨髓状细胞系歪曲.
主要成果:
- 与年龄相关的TNF在老WT接受者中显著增加了扩展的Tet2-/-细胞,有利于髓状血统.
- 这种扩张在老TNF-/-接受者小鼠中减少,表明TNF的重要作用.
- 患有CHIP和类风湿性关节炎的人类患者表现出突变细胞对TNF阻塞的敏感性.
结论:
- TNF信号传递对于TET2-突变骨髓克隆的体内扩张至关重要.
- 准TNF可能是一个可行的策略,以减少TET2突变CHIP的负担.
- 这项研究提供了第一个证据,证明TNF在驱动TET2突变CHIP扩张中的因果作用.
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