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研究揭示骨髓增生异常综合症发病机制

文章来源:admin    时间:2020-04-24

  

本期文章:《自然—免疫学》:Online/在线发表

美国辛辛那提儿童医院医学中心Daniel T. Starczynowski研究团队发现,对炎症的适应性反应有助于持续的骨髓生成,并在骨髓增生异常综合症造血干细胞中赋予竞争优势。这一研究成果于2020年4月20日在线发表在《自然—免疫学》上。

研究人员表示,尽管有证据表明骨髓增生异常综合症(MDS)中存在慢性炎症,并且MDS造血干细胞和祖细胞(HSPC)中Toll样受体(TLR)信号的细胞失调,但是MDS HSPC在炎症环境中比正常HSPC更具有竞争优势的机制仍然不明确。

研究人员发现慢性炎症是MDS HSPC竞争优势和疾病进展的决定因素。与正常HSPC相比,MDS HSPC的细胞应答涉及非经典NF-κB途径的信号传导,从而保护了这些细胞免于慢性炎症。

在响应炎症时,MDS HSPCs从经典的NF-κB信号转为非经典的NF-κB信号,该过程依赖于TLR-TRAF6介导的A20激活。 TLR-TRAF6诱导的HSPC竞争优势可以通过敲除A20或抑制非经典NF-κB途径来恢复。

这些发现揭示了MDS HSPC克隆优势的机制,并表明干扰非经典NF-κB信号传导可以阻止MDS进展。

附:英文原文

Title: Adaptive response to inflammation contributes to sustained myelopoiesis and confers a competitive advantage in myelodysplastic syndrome HSCs

Author: Tomoya Muto, Callum S. Walker, Kwangmin Choi, Kathleen Hueneman, Molly A. Smith, Zartash Gul, Guillermo Garcia-Manero, Averil Ma, Yi Zheng, Daniel T. Starczynowski

Issue&Volume: 2020-04-20

Abstract: Despite evidence of chronic inflammation in myelodysplastic syndrome (MDS) and cell-intrinsic dysregulation of Toll-like receptor (TLR) signaling in MDS hematopoietic stem and progenitor cells (HSPCs), the mechanisms responsible for the competitive advantage of MDS HSPCs in an inflammatory milieu over normal HSPCs remain poorly defined. Here, we found that chronic inflammation was a determinant for the competitive advantage of MDS HSPCs and for disease progression. The cell-intrinsic response of MDS HSPCs, which involves signaling through the noncanonical NF-κB pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-κB signaling, a process that was dependent on TLR-TRAF6-mediated activation of A20. The competitive advantage of TLR-TRAF6-primed HSPCs could be restored by deletion of A20 or inhibition of the noncanonical NF-κB pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-κB signaling could prevent MDS progression.

DOI: 10.1038/s41590-020-0663-z

Source: https://www.nature.com/articles/s41590-020-0663-z

期刊信息

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex

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