Institut National de la Santé et de la Recherche Médicale (INSERM), U1009, 114 rue Edouard Vaillant, 94805 Villejuif, France.
Cell Death Dis. 2012 Oct 4;3(10):e396. doi: 10.1038/cddis.2012.137.
The chemokine receptor CXCR4 favors the interaction of acute myeloid leukemia (AML) cells with their niche but the extent to which it participates in pathogenesis is unclear. Here, we show that CXCR4 expression at the surface of leukemic cells allowed distinguishing CXCR4 (high) from CXCR4(neg/low) AML patients. When high levels of CXCR4 are expressed at the surface of AML cells, blocking the receptor function with small molecule inhibitors could promote leukemic cell death and reduce NOD/Shi-scid/IL-2Rγ(null) (NOG) leukemia-initiating cells (LICs). Conversely, these drugs had no efficacy when AML cells do not express CXCR4 or when they do not respond to chemokine CXC motif ligand 12 (CXCL12). Functional analysis showed a greater mobilization of leukemic cells and LICs in response to drugs, suggesting that they target the interaction between leukemic cells and their supportive bone marrow microenvironment. In addition, increased apoptosis of leukemic cells in vitro and in vivo was observed. CXCR4 expression level on AML blast cells and their migratory response to CXCL12 are therefore predictive of the response to the inhibitors and could be used as biomarkers to select patients that could potentially benefit from the drugs.
趋化因子受体 CXCR4 有利于急性髓系白血病 (AML) 细胞与其龛位的相互作用，但它在发病机制中的参与程度尚不清楚。在这里，我们表明，白血病细胞表面的 CXCR4 表达可区分 CXCR4（高）和 CXCR4（低/无）AML 患者。当 AML 细胞表面表达高水平的 CXCR4 时，用小分子抑制剂阻断受体功能可以促进白血病细胞死亡并减少 NOD/Shi-scid/IL-2Rγ(null) (NOG) 白血病起始细胞 (LIC)。相反，当 AML 细胞不表达 CXCR4 或对趋化因子 CXC 基序配体 12 (CXCL12) 无反应时，这些药物则没有疗效。功能分析显示，对药物的反应中，白血病细胞和 LICs 的动员更多，这表明它们靶向白血病细胞与其支持性骨髓微环境之间的相互作用。此外，还观察到体外和体内白血病细胞的凋亡增加。因此，AML 原始细胞上的 CXCR4 表达水平及其对 CXCL12 的迁移反应可预测对抑制剂的反应，可作为生物标志物来选择可能从药物中受益的患者。
