研究揭示骨髓增生異常綜合症發病機制
作者：
小柯機器人發布時間：2020/4/23 13:31:49
美國辛辛那提兒童醫院醫學中心Daniel T. Starczynowski研究團隊發現，對炎症的適應性反應有助於持續的骨髓生成，並在骨髓增生異常綜合症造血幹細胞中賦予競爭優勢。這一研究成果於2020年4月20日在線發表在《自然—免疫學》上。
研究人員表示，儘管有證據表明骨髓增生異常綜合症（MDS）中存在慢性炎症，並且MDS造血幹細胞和祖細胞（HSPC）中Toll樣受體（TLR）信號的細胞失調，但是MDS HSPC在炎症環境中比正常HSPC更具有競爭優勢的機制仍然不明確。
研究人員發現慢性炎症是MDS HSPC競爭優勢和疾病進展的決定因素。與正常HSPC相比，MDS HSPC的細胞應答涉及非經典NF-κB途徑的信號傳導，從而保護了這些細胞免於慢性炎症。
在響應炎症時，MDS HSPCs從經典的NF-κB信號轉為非經典的NF-κB信號，該過程依賴於TLR-TRAF6介導的A20激活。 TLR-TRAF6誘導的HSPC競爭優勢可以通過敲除A20或抑制非經典NF-κB途徑來恢復。
這些發現揭示了MDS HSPC克隆優勢的機制，並表明幹擾非經典NF-κB信號傳導可以阻止MDS進展。
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