A CXCR4 antagonist leads to tumor suppression by activation of immune cells in a leukemia-induced microenvironment
A CXCR4 antagonist leads to tumor suppression by activation of immune cells in a leukemia-induced microenvironment
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DOI：
10.3892/or.2015.4297
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发表时间：
2015-12-01
期刊：
影响因子：
4.2
通讯作者：
Kim, Se-Hoon
中科院分区：
文献类型：
--
作者：
Han, A-Reum;Lee, Ji Yoon;Kim, Se-Hoon
骨髓微环境（BMM）提供了一个保护性生态位，支持正常和白血病造血干细胞的生长和存活。 SDF-1/CXCR4 相互作用对于调节骨髓 (BM) 中造血细胞的归巢和保留至关重要，从而导致化疗耐药性增加。 SDF-1/CXCR4 在原始细胞和 BMM 之间的交叉相互作用（以防止白血病细胞的保留和动员）以及正常造血（包括免疫细胞的发育）中发挥着关键作用。我们发现 CXCR4 拮抗剂 plerixafor 可降低 CXCR4 表达水平并抑制 SDF-1 诱导的白血病细胞迁移。此外，在急性髓性白血病（AML）小鼠模型中，由于白血病细胞对阿糖胞苷（Ara-C）等化疗药物的敏感性增加，普乐沙福抑制白血病细胞与BMM之间的相互作用增强了免疫细胞的细胞毒活性，这表明BMM通过免疫细胞激活发挥生物学效应。由于 BMM 的改变可促进白血病细胞的保留和存活，因此靶向微环境被认为是根除耐药白血病细胞的先进策略。这项研究表明，CXCR4 抑制对肿瘤微环境中的急变抑制和免疫细胞功能的影响以及普乐沙福化疗代表了一种针对白血病生态位的先进治疗策略。
The bone marrow microenvironment (BMM) provides a protective niche that supports growth and survival of normal and leukemic hematopoietic stem cells. The SDF-1/CXCR4 interaction is critical for regulation of homing to and retention of hematopoietic cells in the bone marrow (BM), which leads to increased chemoresistance. SDF-1/CXCR4 plays pivotal roles in cross-interactions between blasts and the BMM to prevent retention and mobilization of leukemic cells, as well as in normal hematopoiesis including the development of immune cells. We show that the CXCR4 antagonist, plerixafor, decreased the level of CXCR4 expression and inhibited SDF-1-induced migration of leukemic cells. Further, the inhibition of the interaction between leukemic cells and the BMM by the plerixafor enhanced cytotoxic activity of immune cells as a result of increased susceptibility of leukemic cells to chemotherapeutic agents such as cytosine arabinoside (Ara-C) in a mouse model of acute myeloid leukemia (AML), suggesting biological effects of the BMM through immune cell activation. Because alterations in the BMM promote retention and survival of leukemic cells, targeting the niche is regarded as an advanced strategy to eradicate drug-resistant leukemic blasts. This study demonstrates that the effects of CXCR4 inhibition on blast suppression and immune cell function in the tumor microenvironment and chemotherapy with plerixafor represents an advanced therapeutic strategy of targeting the leukemic niche.