DDX5-targeting fully human monoclonal autoantibody inhibits proliferation and promotes differentiation of acute promyelocytic leukemia cells by increasing ROS production
DDX5-targeting fully human monoclonal autoantibody inhibits proliferation and promotes differentiation of acute promyelocytic leukemia cells by increasing ROS production
复制标题
DDX5 靶向全人单克隆自身抗体通过增加 ROS 产生抑制增殖并促进急性早幼粒细胞白血病细胞分化
DOI：
10.1038/s41419-020-02759-5
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发表时间：
2020-07-20
影响因子：
9
通讯作者：
Pan，Xiao-Ben
中科院分区：
文献类型：
--
作者：
Wu，Jing;You，Yan-Qiu;Pan，Xiao-Ben
急性早幼粒细胞白血病（APL）治疗涉及对恶性肿瘤和正常细胞均具有细胞毒性的化合物。复发的 APL 对后续化疗有抵抗力。需要新的药物以最小的毒性选择性地杀死 APL 细胞。 DDX5 已被认为是抑制急性髓系白血病 (AML) 的新靶点。然而，DDX5 在 APL 中的作用仍然难以捉摸。这里制备了一种靶向DDX5的全人单克隆自身抗体，以2F5命名。结果表明，2F5选择性抑制APL细胞增殖，且对正常中性粒细胞和组织没有毒性。此外，2F5 被证实可诱导 APL 细胞 G0/G1 期阻滞，并促进 APL 细胞分化，同时减少 DDX5 表达和增加活性氧 (ROS) 产生。通过 siRNA 敲低 DDX5 还可以抑制 APL 细胞的增殖、促进细胞分化并增强 ROS 的产生。然而，ROS 抑制剂逆转了 2F5 对 APL 细胞中 DDX5 和 ROS 的影响。因此，我们得出结论，靶向 DDX5 的 2F5 抑制 APL 细胞增殖，并通过诱导 ROS 促进细胞分化。 2F5显示了全人源单克隆自身抗体在APL中的治疗价值，为复发/难治性APL的治疗提供了一种新颖有效的方法。
Acute promyelocytic leukemia (APL) therapy involves the compounds cytotoxic to both malignant tumor and normal cells. Relapsed APL is resistant to subsequent chemotherapy. Novel agents are in need to kill APL cells selectively with minimal toxicity. DDX5 has been recognized to be a novel target to suppress acute myeloid leukemia (AML). However, the role of DDX5 remains elusive in APL. Here a DDX5-targeting fully human monoclonal autoantibody named after 2F5 was prepared. It is demonstrated that 2F5 selectively inhibited APL cell proliferation without toxicity to normal neutrophil and tissues. Moreover, 2F5 was confirmed to induce G0/G1 phase arrest in APL cells, and promote APL cell differentiation combined with decreased DDX5 expression and increased reactive oxygen species (ROS) production. Knockdown of DDX5 by siRNA also inhibited proliferation, promoted cell differentiation and enhanced ROS production in APL cells. However, the ROS inhibitor reversed the effects of 2F5 on DDX5 and ROS in APL cells. Thus, we conclude that DDX5-targeting 2F5 inhibits APL cell proliferation, and promotes cell differentiation via induction of ROS. 2F5 showed the therapeutic value of fully human monoclonal autoantibody in APL, which provides a novel and valid approach for treatment of relapse/refractory APL.