甲氧氯普胺治疗阻断 CD93 信号介导的慢性髓系白血病干细胞自我更新。
Metoclopramide treatment blocks CD93-signaling-mediated self-renewal of chronic myeloid leukemia stem cells.
机构信息
Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
出版信息
Cell Rep. 2021 Jan 26;34(4):108663. doi: 10.1016/j.celrep.2020.108663.
Self-renewal is a key characteristic of leukemia stem cells (LSCs) responsible for the development and maintenance of leukemia. In this study, we identify CD93 as an important regulator of self-renewal and proliferation of murine and human LSCs, but not hematopoietic stem cells (HSCs). The intracellular domain of CD93 promotes gene transcription via the transcriptional regulator SCY1-like pseudokinase 1 independently of ligation of the extracellular domain. In a drug library screen, we identify the anti-emetic agent metoclopramide as an efficient blocker of CD93 signaling. Metoclopramide treatment reduces murine and human LSCs in vitro and prolongs survival of chronic myeloid leukemia (CML) mice through downregulation of pathways related to stemness and proliferation in LSCs. Overall, these results identify CD93 signaling as an LSC-specific regulator of self-renewal and proliferation and a targetable pathway to eliminate LSCs in CML.
自我更新是白血病干细胞（LSCs）的一个关键特征，负责白血病的发展和维持。在这项研究中，我们确定 CD93 是调节鼠类和人类 LSCs 自我更新和增殖的重要调控因子，但不是造血干细胞（HSCs）。CD93 的细胞内域通过转录调节因子 SCY1 样假激酶 1 促进基因转录，而不依赖于细胞外域的连接。在药物文库筛选中，我们发现止吐药甲氧氯普胺是 CD93 信号的有效阻断剂。甲氧氯普胺治疗通过下调 LSCs 中与干性和增殖相关的途径，减少体外鼠类和人类 LSCs，并延长慢性髓性白血病（CML）小鼠的存活时间。总的来说，这些结果表明 CD93 信号是 LSC 自我更新和增殖的特异性调节因子，是消除 CML 中 LSC 的一个有针对性的靶点。
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