Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
Nat Immunol. 2020 May;21(5):535-545. doi: 10.1038/s41590-020-0663-z. Epub 2020 Apr 20.
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.
尽管骨髓增生异常综合征（MDS）存在慢性炎症的证据，并且 MDS 造血干细胞和祖细胞（HSPCs）中 Toll 样受体（TLR）信号的细胞内调节存在障碍，但导致 MDS HSPCs 在炎症环境中相对于正常 HSPCs 具有竞争优势的机制仍未完全明确。在这里，我们发现慢性炎症是 MDS HSPCs 竞争优势和疾病进展的决定因素。与正常 HSPCs 相比，MDS HSPCs 的细胞内反应涉及非经典 NF-κB 途径的信号转导，从而保护这些细胞免受慢性炎症的影响。MDS HSPCs 对炎症的反应从经典 NF-κB 信号转导切换为非经典 NF-κB 信号转导，这一过程依赖于 TLR-TRAF6 介导的 A20 的激活。通过删除 A20 或抑制非经典 NF-κB 途径，可以恢复 TLR-TRAF6 引发的 HSPCs 的竞争优势。这些发现揭示了 MDS HSPCs 克隆优势的机制基础，并表明干扰非经典 NF-κB 信号可能阻止 MDS 的进展。
