Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes.
Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes.
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DOI：
10.1038/leu.2015.69
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发表时间：
2015-07
期刊：
影响因子：
11.4
通讯作者：
Garcia-Manero G
中科院分区：
文献类型：
--
作者：
Gañán-Gómez I;Wei Y;Starczynowski DT;Colla S;Yang H;Cabrero-Calvo M;Bohannan ZS;Verma A;Steidl U;Garcia-Manero G
骨髓增生异常综合征（MDS）是一组异质性克隆性血液系统恶性肿瘤，其特征为骨髓（BM）造血功能缺陷以及髓内细胞凋亡的发生。在过去十年中，对患者关键基因和表观遗传学改变的鉴定提高了我们对该疾病病理生理学的理解。然而，导致MDS发病的具体分子机制在很大程度上仍不清楚。最近，已经获得了支持先天性免疫异常在MDS中直接作用的重要证据，包括鉴定出在骨髓造血干细胞和祖细胞中过度表达或组成性激活的多个关键调节因子。越来越多的实验结果表明，这些分子的失调导致患者骨髓中造血异常、细胞死亡和增殖失衡，并在MDS的发病机制中起重要作用。此外，有令人信服的证据表明，先天性免疫和炎症信号的失调也会影响免疫系统的其他细胞以及骨髓微环境，这些细胞与造血前体细胞建立异常联系并促成MDS表型。因此，先天性免疫和炎症信号的失调应被视为MDS发病机制中的驱动力之一。在本文中，我们回顾并更新了该领域的进展，总结了最新研究的结果并讨论了其临床意义。
Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.