ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis
ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis
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DOI：
10.1007/s12032-021-01466-1
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发表时间：
2021-03-01
期刊：
影响因子：
3.4
通讯作者：
Pinheiro, Ronald Feitosa
中科院分区：
文献类型：
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作者：
Germano de Oliveira, Roberta Taiane;Alves Cordeiro, Joao Victor;Pinheiro, Ronald Feitosa
Toll样受体在高达50%的骨髓增生异常综合征（MDS）患者中突变或过表达。内源性逆转录病毒（ERV）触发TLR 3，导致干扰素调节基因（IRF）激活。我们评估了ERVs-TLR 3-IRF轴激活是否与MDS发病机制相关，并且我们还使用GEPIA数据库对30种癌症类型中的ERVs、TLR 3和IRF基因表达进行了详细的癌症分析。对79例MDS患者的骨髓样本进行了细胞遗传学和TLR 3、ERVK 6、ERVW-1、ERV 3 -1、IRF 3和IRF 7的定量实时PCR评价。与无红细胞生成异常的患者相比，具有红细胞生成异常的患者显示更高的TLR 3（p = 0.035）、ERVK 6（p = 0.001）、ERVW 1（p = 0.045）和ERV 3 -1（p = 0.016）表达。干扰素调节因子IRF 3和IRF 7的上调与MDS的不良预后标志物相关，如> 10%的原始细胞（p = 0.003-IRF 3; p = 0.009-IRF 7），血小板计数低（< 50.000/mm（3））（p = 0.001-IRF 3; p = 0.021-IRF 7）、输血依赖（p = 0.014-IRF 3）和染色体异常（p = 0.036-IRF 7）。我们发现ERVK 6-ERVW 1之间有很强的相关性，（r = 0.800; r（2）= 0.640; p = 0.000），ERVW1-ERV3-1（r = 0.715; r（2）= 0.511; p = 0.000），和IRF 7-IRF 3（r = 0.567; r（2）= 0.321; p = 0.000）和ERVK 6-ERV 3 -1之间的中度相关性。（r = 0.485; r（2）= 0.235; p = 0.000），ERVW1-IRF7（r = 0.389; r（2）= 0.151; p = 0.001），ERVW1-IRF3（r = 0.357; r（2）= 0.127; p = 0.004）、ERV3-1-IRF7（r = 0.314; r（2）= 0.098; p = 0.009）和ERV3-1-IRF3（r = 0.324; r（2）= 0.104; p = 0.007）。在30种癌症类型中使用GEPIA数据库，我们检测到MDS中的典型上调模式。我们认为ERVs激活TLR 3与导致骨髓衰竭的MDS发病机制有关。[图形]。
Toll-like receptors are mutated or overexpressed in up to 50% of patients with myelodysplastic syndrome (MDS). Endogenous retroviruses (ERV) trigger TLR3 leading to interferon regulatory genes (IRFs) activation. We evaluated if the ERVs-TLR3-IRF axis activation would be linked to MDS pathogenesis and we also conducted a detailed cancer analysis of the ERVs, TLR3 and IRFs gene expression in 30 cancer types using GEPIA database. Seventy-nine bone marrow samples from patients with MDS were evaluated for cytogenetics and quantitative real-time PCR of TLR3,ERVK6, ERVW-1, ERV3-1, IRF3 and IRF7. Patients with dyserythropoiesis showed higher TLR3 (p = 0.035), ERVK6 (p = 0.001), ERVW1 (p = 0.045) and ERV3-1 (p = 0.016) expression than patients without dyserythropoiesis. Upregulation of Interferon Regulatory Factors, IRF3 and IRF7, was associated with poor prognostic markers in MDS such as > 10% of blasts (p = 0.003-IRF3; p = 0.009-IRF7), low platelets count (< 50.000/mm(3)) (p = 0.001-IRF3; p = 0.021-IRF7), transfusion dependence (p = 0.014-IRF3) and chromosomal abnormalities (p = 0.036-IRF7). We found strong correlations between ERVK6-ERVW1 (r = 0.800; r(2) = 0.640; p = 0.000), ERVW1-ERV3-1 (r = 0.715; r(2) = 0.511; p = 0.000), and IRF7-IRF3 (r = 0.567; r(2) = 0.321; p = 0.000) and moderate correlation between ERVK6-ERV3-1(r = 0.485; r(2) = 0.235; p = 0.000), ERVW1-IRF7 (r = 0.389; r(2) = 0.151; p = 0.001), ERVW1-IRF3 (r = 0.357; r(2) = 0.127; p = 0.004), ERV3-1-IRF7 (r = 0.314; r(2) = 0.098; p = 0.009), and ERV3-1-IRF3 (r = 0.324; r(2) = 0.104; p = 0.007). Using GEPIA Database in 30 cancer types, we detected a typical pattern of upregulation as here presented in MDS. We suggest TLR3 activation by ERVs is linked to MDS pathogenesis leading to bone marrow failure.[GRAPHICS].