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

被引:119
作者
Muto, Tomoya [1 ]
Walker, Callum S. [1 ]
Choi, Kwangmin [1 ]
Hueneman, Kathleen [1 ]
Smith, Molly A. [1 ]
Gul, Zartash [2 ]
Garcia-Manero, Guillermo [3 ]
Ma, Averil [4 ]
Zheng, Yi [1 ,5 ]
Starczynowski, Daniel T. [1 ,5 ,6 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA
[2] Univ Cincinnati, Dept Internal Med, Cincinnati, OH USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
[4] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[5] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA
[6] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45221 USA
基金
美国国家卫生研究院; 日本学术振兴会;
关键词
NF-KAPPA-B; GENE-EXPRESSION; CUTTING EDGE; TET2; CELLS; PATHWAY; MICE; IDENTIFICATION; PATHOGENESIS; INVOLVEMENT;
D O I
10.1038/s41590-020-0663-z
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-kappa B pathway, protected these cells from chronic inflammation as compared to normal HSPCs. In response to inflammation, MDS HSPCs switched from canonical to noncanonical NF-kappa B 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-kappa B pathway. These findings uncover the mechanistic basis for the clonal dominance of MDS HSPCs and indicate that interfering with noncanonical NF-kappa B signaling could prevent MDS progression. Starczynowski and colleagues show that myelodysplastic syndrome HSPCs have a competitive advantage as compared to normal HSPCs during chronic inflammation due to a switch from canonical to noncanonical signaling for the activation of NF-kappa B.
引用
收藏
页码:535 / +
页数:21
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