Defective p38 mitogen-activated protein kinase signaling impairs chemotaxic but not proliferative responses to stromal-derived factor-1α in acute lymphoblastic leukemia
Defective p38 mitogen-activated protein kinase signaling impairs chemotaxic but not proliferative responses to stromal-derived factor-1α in acute lymphoblastic leukemia
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DOI：
10.1158/0008-5472.can-04-3402
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发表时间：
2005-04-15
期刊：
影响因子：
11.2
通讯作者：
Bradstock, KF
中科院分区：
文献类型：
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作者：
Bendall, LJ;Baraz, R;Bradstock, KF
趋化因子基质衍生因子-1 α（SDF-1 α）调节白血病细胞的运动性和增殖;然而，这些功能在白血病生长和传播中的重要性尚不清楚。我们检测了27例急性淋巴细胞白血病（ALL）患者的SDF-1 α介导的细胞反应。虽然大多数病例的细胞显示出对SDF-1 α的趋化性和增殖反应，但一部分病例没有发生对SDF-1 α的趋化反应，同时仍证明在基质支持的培养物中增殖依赖于SDF-1 α。这种趋化性缺陷与SDF-1 α诱导的p38丝裂原活化蛋白激酶（MAPK）磷酸化的缺失以及SDF-1 α诱导的β 1整合素介导的粘附增强有关。通过磷酸肌醇3-激酶和MEK的信号传导不受影响。在非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠中，未观察到CXCR 4表达与趋化功能、体外迁移至骨髓基质层以及白血病细胞植入之间的相关性。这项研究表明，通过p38 MAPK的信号传导是ALL细胞趋化性所必需的，但不是增殖所必需的，并且对SDF-1 α的趋化反应的丧失不会阻碍NOD/SCID小鼠的植入。
The chemokine stromal-derived factor-1 alpha (SDF-1 alpha) regulates leukemic cell motility and proliferation; however, the importance of these functions in the growth and dissemination of leukemia is unclear. We examined SDF-1 alpha-mediated responses of cells from 27 cases of acute lymphoblastic leukemia (ALL). Although cells from the majority of cases showed chemotactic and proliferative responses to SDF-1 alpha, a subset of cases did not undergo chemotaxis in response to SDF-1 alpha, while still demonstrating dependence on SDF-1 alpha for proliferation in stroma-supported cultures. This chemotactic defect was associated with an absence of phosphorylation ofp38 mitogen-activated protein kinase (MAPK) induced by SDF-1 alpha, and of SDF-1 alpha-induced augmentation of beta(1) integrin-mediated adhesion. Signaling through phosphoinositide 3-kinase and MEK was not affected. No correlation was observed between CXCR4 expression and chemotactic function, in vitro migration into bone marrow stromal layers, and engraftment of leukemic cells in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This study suggests that signaling through p38 MAPK is required for ALL cell chemotaxis but not for proliferation, and that the loss of a chemotactic response to SDF-1 alpha does not impede engraftment in NOD/SCID mice.