Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1.
Activation of the complement cascade enhances motility of leukemic cells by downregulating expression of HO-1.
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DOI：
10.1038/leu.2016.198
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发表时间：
2017-02
期刊：
影响因子：
11.4
通讯作者：
Ratajczak MZ
中科院分区：
文献类型：
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作者：
Abdelbaset-Ismail A;Borkowska-Rzeszotek S;Kubis E;Bujko K;Brzeźniakiewicz-Janus K;Bolkun L;Kloczko J;Moniuszko M;Basak GW;Wiktor-Jedrzejczak W;Ratajczak MZ
补体级联反应（ComC）作为先天免疫的重要组成部分，参与正常造血干/祖细胞（HSPC）从骨髓（BM）向外周血的动员和向BM的归巢。尽管ComC切割片段单独不化学吸引正常HSPC，但我们发现白血病细胞系以及来自慢性髓性白血病和急性髓性白血病患者的克隆原性母细胞通过趋化性和增加的粘附对C3和C5切割片段强烈响应。这一发现得到了来自人恶性造血细胞系和患者胚细胞的细胞中C3 a和C5 a受体在mRNA水平的检测的支持。（逆转录-聚合酶链反应）和蛋白水平（荧光激活细胞分选），并且通过证明这些受体通过p42/44和p38促分裂原激活蛋白激酶（MAPK）的磷酸化响应C3 a和C5 a的刺激，和蛋白激酶B（PKB/AKT）。我们还发现，诱导型血红素加氧酶1（HO-1）是ComC介导的白血病细胞运输的负调节因子，C3或C5裂解片段刺激白血病细胞激活p38 MAPK，其下调HO-1表达，使细胞更具移动的。我们的结论是，在白血病/淋巴瘤患者（例如，作为伴随感染的结果）的ComC的激活增强恶性细胞的运动性，并有助于他们的传播中的p38 MAPK-HO-1依赖的方式。因此，当ComC被激活时，通过小分子调节剂抑制p38 MAPK或上调HO-1将对改善白血病/淋巴瘤细胞的细胞迁移介导的扩增具有有益作用。
As a crucial arm of innate immunity, the complement cascade (ComC) is involved both in mobilization of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood and in their homing to BM. Despite the fact that ComC cleavage fragments alone do not chemoattract normal HSPCs, we found that leukemia cell lines as well as clonogenic blasts from chronic myeloid leukemia and acute myeloid leukemia patients respond robustly to C3 and C5 cleavage fragments by chemotaxis and increased adhesion. This finding was supported by the detection of C3a and C5a receptors in cells from human malignant hematopoietic cell lines and patient blasts at the mRNA (reverse transcriptase-polymerase chain reaction) and protein level (fluorescence-activated cell sorting), and by the demonstration that these receptors respond to stimulation by C3a and C5a by phosphorylation of p42/44 and p38 mitogen-activated protein kinases (MAPK), and protein kinase B (PKB/AKT). We also found that inducible heme oxygenase 1 (HO-1) is a negative regulator of ComC-mediated trafficking of leukemic cells, and that stimulation of leukemic cells by C3 or C5 cleavage fragments activates p38 MAPK, which downregulates HO-1 expression, rendering cells more mobile. We conclude that activation of the ComC in leukemia/lymphoma patients (for example, as a result of accompanying infections) enhances the motility of malignant cells and contributes to their spread in a p38 MAPK–HO-1-dependent manner. Therefore, inhibition of p38 MAPK or upregulation of HO-1 by small-molecule modulators would have a beneficial effect on ameliorating cell migration-mediated expansion of leukemia/lymphoma cells when the ComC becomes activated.