CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment
CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment
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DOI：
10.1038/sj.leu.2404684
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发表时间：
2007-06-01
期刊：
影响因子：
11.4
通讯作者：
Bendall, L. J.
中科院分区：
文献类型：
--
作者：
Juarez, J.;Dela Pena, A.;Bendall, L. J.
CXCL 12在B细胞祖细胞急性淋巴细胞白血病（ALL）的骨髓（BM）归巢和生长中的作用已被确立。然而，调节CXCL 12/CXCR 4相互作用对ALL细胞在支持性BM微环境中的保留以及ALL细胞在体内的扩增和传播的影响尚未被研究。我们使用人类儿童和小鼠白血病的小鼠模型和特异性肽和小分子CXCR 4拮抗剂来研究CXCL 12/CXCR 4在体内白血病发展中的重要性。CXCR 4拮抗剂动员ALL细胞进入外周血（PB）。与对照治疗的动物相比，在五个测试病例中的三个中，向患有白血病的小鼠延长施用CXCR 4拮抗剂导致动物的PB和脾脏中的白血病细胞数量减少。在所有发生这种情况的病例中，ALL细胞向髓外部位（包括肝脏和肾脏）的播散也显著减少。考虑到基质层对化学治疗剂活性的抑制作用以及CXCL 12拮抗剂与化学治疗剂在体外的相互作用，这提高了使用这些药剂来增强当前化学治疗方案的效果的可能性。
The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.