Mesenchymal COX2-PG secretome engages NR4A-WNT signalling axis in haematopoietic progenitors to suppress anti-leukaemia immunity.
Mesenchymal COX2-PG secretome engages NR4A-WNT signalling axis in haematopoietic progenitors to suppress anti-leukaemia immunity.
复制标题
间充质Cox2-PG分粒子与造血祖细胞中的NR4A-WNT信号轴接合，以抑制抗leukaemia的免疫力。
DOI：
10.1111/bjh.15548
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发表时间：
2018-11
影响因子：
6.5
通讯作者：
Du W
中科院分区：
文献类型：
--
作者：
Wu L;Amarachintha S;Xu J;Oley F Jr;Du W
骨髓（BM）微环境（生态位）在支持正常/异常造血中起着重要作用。我们研究了白血病间充质生态位和造血干细胞和祖细胞（HSPCs）之间的相互作用，使用范可尼贫血（FA），一种遗传性疾病的特点是BM失败和白血病的模型。健康供体HSPC与来自患有急性髓性白血病（AML）的FA患者的间充质基质细胞（MSC）共培养，在非肥胖糖尿病重度联合免疫缺陷IL-2γ−/−/SGM 3受体中表现出更高的人类植入和骨髓扩增。非靶向代谢组学分析显示FA骨髓增生异常综合征（MDS）和AML患者的MSC中的前列腺素（PGs）进行性升高。炎性环氧合酶2（COX 2）抑制后PG分泌减少可改善HSPC/骨髓扩张。转录组分析显示FA-AML-MSC-共培养的CD 34+细胞中参与NR 4A家族转录因子（TF）和WNT/β-catenin信号通路的基因失调。COX 2抑制导致NR 4A TF和WNT信号传导基因表达显著降低。在机制上，NR 4A 1和NR 4A 2协同激活CTNNB 1基因启动子。在AML-MSC-共培养的-CD 34+细胞中敲低CTNNB 1或NR 4A 1增加了白血病反应性T效应细胞的产生并挽救了抗白血病免疫力。总之，这些发现表明白血病间充质生态位和HSPC之间的特异性相互作用协调了一种新的COX 2/PG-NR 4A/WNT信号传导轴，将炎症，细胞代谢和癌症免疫联系起来。
The bone marrow (BM) microenvironment (niche) plays important roles in supporting normal/abnormal haematopoiesis. We investigated the interaction between leukaemic mesenchymal niche and haematopoietic stem and progenitor cells (HSPCs) using the model of Fanconi anaemia (FA), a genetic disorder characterized by BM failure and leukaemia. Healthy donor HSPCs co-cultured on mesenchymal stromal cells (MSCs) derived from FA patients with acute myeloid leukaemia (AML) exhibited higher human engraftment and myeloid expansion in Non-obese diabetic severe combined immunodeficiency IL-2γ−/−/SGM3 recipients. Untargeted metabolomics analysis revealed the progressively elevated prostaglandins (PGs) in the MSCs of FA patients with myelodysplastic syndromes (MDS) and AML. Reduced secretion of PGs subsequent to inflammatory cyclooxygenase 2 (COX2) inhibition ameliorated HSPC/myeloid expansion. Transcriptome analysis demonstrated dysregulation of genes involved in the NR4A family of transcription factors (TFs) and WNT/β-catenin signalling pathway in FA-AML-MSC-co-cultured-CD34+ cells. COX2 inhibition led to significantly decreased NR4A TFs and WNT signalling genes expression. Mechanistically, NR4A1 and NR4A2 synergistically activate the CTNNB1 gene promoter. Knocking down CTNNB1 or NR4A1 in AML-MSC-co-cultured-CD34+ cells increased leukaemia-reactive T-effector cells production and rescued anti-leukaemia immunity. Together, these findings suggest that specific interactions between leukaemic mesenchymal niche and HSPCs orchestrate a novel COX2/PG-NR4A/WNT signalling axis, connecting inflammation, cellular metabolism and cancer immunity.
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影响因子：
64.8
作者：
Marson, Alexander;Kretschmer, Karsten;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
3.7
作者：
Fuerer C;Nusse R
通讯作者：
Nusse R
影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI
影响因子：
4.8
作者：
Dalle, J-H
通讯作者：
Dalle, J-H
DOI：
10.1002/stem.2100
发表时间：
2015-11
期刊：
Stem cells (Dayton, Ohio)
影响因子：
--
作者：
Amarachintha S;Sertorio M;Wilson A;Li X;Pang Q
通讯作者：
Pang Q