Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma
Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma
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DOI：
10.1182/blood-2006-07-035857
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Ghobrial, Irene M.
中科院分区：
文献类型：
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作者：
Alsayed, Yazan;Ngo, Hai;Ghobrial, Irene M.
多发性骨髓瘤(MM)细胞迁移和归巢到骨髓的机制还不是很清楚。在本研究中，我们试图确定趋化因子SDF-1(CXCL12)及其受体CXCR4对MM细胞迁移和归巢的影响。我们证明了CXCR4在外周血中的高水平差异表达，并在骨髓中下调表达，以响应高水平的SDF-1。共聚焦显微镜证实SDF-1诱导MM细胞的运动、内化和细胞骨架重排。特异性CXCR4抑制剂AMD3100和抗CXCR4抗体MAB171在体外可抑制MM细胞的迁移。CXCR4基因敲除实验表明，依赖SDF-1的迁移受PI3K和ERK/MAPK信号通路的调控，而不受p38MAPK信号通路的调控。此外，我们用体内流式细胞术、体内共聚焦显微镜和全身生物发光成像证明了AMD3100抑制了MM细胞归巢到骨髓壁龛。因此，这项研究表明SDF-1/CXCR4是MM归巢的关键调节因子，并为该途径的抑制剂在未来的临床试验中用于消除MM贩运提供了框架。
The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the PI3K and ERK/MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.