VLA4 in Acute Lymphoblastic Leukemia

VLA4 in Acute Lymphoblastic Leukemia
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VLA4 在急性淋巴细胞白血病中的作用

DOI:
10.1007/978-1-4939-1393-0_34
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发表时间:
2015
期刊:
影响因子:
--
通讯作者:
Kim YM
Kim YM
中科院分区:
--
文献类型:
--
作者:
Bonig H;Kim YM

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细胞减灭药物的化疗耐药性和脱靶长期毒性仍然是当前前 B 细胞急性淋巴细胞白血病 (ALL) 治疗的重大问题。研究表明,化疗耐药性部分是由白血病细胞外源性宿主信号(即来自骨髓环境的信号)促进的。使用功能阻断抗体和遗传模型进行的详细研究已确定 α4β1 整合素、极晚作用整合素 4 (VLA4) 是调节骨髓归巢和正常细胞和白血病细胞主动保留的关键分子。临床前证据表明,干扰 VLA4 介导的 ALL 细胞粘附可以使细胞对化疗敏感。如果这些数据能够在临床试验中得到证实,靶向VLA4可以提高化疗耐药性ALL的治愈率,并且可以减少标准风险白血病的化疗剂量,从而减轻脱靶毒性的急性和长期后遗症。
Chemotherapy resistance and off-target long-term toxicity of the cytoreductive drugs remain significant problems of current therapies for pre-B cell acute lymphoblastic leukemia (ALL). It was shown that chemotherapy resistance is promoted in part by leukemia cell-extrinsic host-derived signals, i.e., by signals emanating from the bone marrow environment. Detailed studies using function-blocking antibodies and genetic models have identified the α4β1integrin, very-late-acting integrin-4 (VLA4), as a critical molecule regulating bone marrow homing and active retention of normal and leukemia cells. Preclinical evidence has been provided that interference with VLA4-mediated adhesion of ALL cells can thus sensitize the cells to chemotherapy. If these data can be corroborated in clinical trials, targeting VLA4 could improve cure rates for chemotherapy-resistant ALL, as well as it might allow for reduction of chemotherapy doses for standard-risk leukemias, thus attenuating acute and long-term sequelae of off-target toxicity.
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