Role of integrin alpha4 in drug resistance of leukemia.
Role of integrin alpha4 in drug resistance of leukemia.
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DOI：
10.3389/fonc.2014.00099
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发表时间：
2014
影响因子：
4.7
通讯作者：
Kim YM
中科院分区：
文献类型：
--
作者：
Shishido S;Bönig H;Kim YM
急性淋巴细胞白血病（ALL）的化疗耐药是一个重要问题，导致一线治疗反应不佳或短暂缓解后复发。经典的抗白血病药物是非特异性细胞周期毒药；一些更现代的药物靶向白血病细胞中的致癌途径，尽管在ALL中这些作用不是很显著。相比之下，在设计针对耐药白血病的新疗法时，微环境与白血病细胞之间的分子相互作用往往被忽视。然而，研究表明，化疗耐药在一定程度上是通过白血病细胞与骨髓（BM）基质细胞的细胞间接触而促进的，也称为细胞粘附介导的耐药（CAM-DR）。对化疗的不完全反应导致耐药克隆存在或不存在可检测到的微小残留病（MRD）。如何解决CAM-DR和MRD的方法仍然难以捉摸。具体来说，使用抗功能抗体和遗传模型的研究已经确定整合素α 4是调节正常和白血病细胞BM归巢和主动保留的关键分子。临床前证据表明，干扰α 4介导的ALL细胞粘附可以使它们对化疗敏感，从而促进MRD环境下ALL细胞的根除。为此，Andreeff及其同事最近提供了白血病细胞中基质诱导和α - 4介导的核因子-κB信号传导的证据，该信号的破坏会耗尽白血病细胞的强生存信号。我们在此回顾了支持靶向alpha4作为治疗耐药白血病的新策略的现有证据。
Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell–cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-κB signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia.