Signal-transducing adapter protein-1 is required for maintenance of leukemic stem cells in CML.
Signal-transducing adapter protein-1 is required for maintenance of leukemic stem cells in CML.
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信号转导接头蛋白 1 是维持 CML 白血病干细胞所必需的。
DOI：
10.1038/s41388-020-01387-9
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发表时间：
2020
期刊：
影响因子：
8
通讯作者：
Kanakura Y.
中科院分区：
文献类型：
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作者：
Toda J;Ichii M;Oritani K;Shibayama H;Tanimura A;Saito H;Yokota T;Motooka D;Okuzaki D;Kitai Y;Muromoto R;Kashiwakura JI;Matsuda T;Hosen N;Kanakura Y.
信号转导衔接蛋白（signal-transducing adapter proteins，STAP）家族参与了多种细胞内信号转导途径，是一种转录因子。我们以前克隆STAP-2作为c-Fms相互作用蛋白，并探讨其对慢性粒细胞白血病（CML）白血病发生的影响。STAP-2与BCR-ABL结合，上调BCR-ABL磷酸化，并激活其下游分子。在这项研究中，我们评估了STAP-1，另一个成员的STAP家族，在CML发病机制中的作用。我们发现，STAP-1的表达在CML患者骨髓中的干细胞（LSC）中异常上调。利用实验模型小鼠，STAP-1的缺失通过诱导LSC的凋亡延长CML小鼠的存活。STAP-1消融导致STAT 5磷酸化状态受损导致抗凋亡基因Bcl-2和Bcl-xL下调。有趣的是，转录组分析表明STAP-1影响与BCR-ABL、JAK 2和PPARγ相关的几种信号通路。这种衔接蛋白不仅直接结合BCR-ABL，而且还结合STAT 5蛋白，显示出STAP-1抑制和BCR-ABL或JAK 2酪氨酸激酶抑制的协同效应。我们的研究结果确定了STAP-1作为CML LSC的调节因子，并表明其是CML的潜在治疗靶点。
The family of signal-transducing adapter proteins (STAPs) has been reported to be involved in a variety of intracellular signaling pathways and implicated as transcriptional factors. We previously cloned STAP-2 as a c-Fms interacting protein and explored its effects on chronic myeloid leukemia (CML) leukemogenesis. STAP-2 binds to BCR-ABL, upregulates BCR-ABL phosphorylation, and activates its downstream molecules. In this study, we evaluated the role of STAP-1, another member of the STAP family, in CML pathogenesis. We found that the expression of STAP-1 is aberrantly upregulated in CML stem cells (LSCs) in patients’ bone marrow. Using experimental model mice, deletion of STAP-1 prolonged the survival of CML mice with inducing apoptosis of LSCs. The impaired phosphorylation status of STAT5 by STAP-1 ablation leads to downregulation of antiapoptotic genes, Bcl-2 and Bcl-xL. Interestingly, transcriptome analyses indicated that STAP-1 affects several signaling pathways related to BCR-ABL, JAK2, and PPARγ. This adapter protein directly binds to not only BCR-ABL, but also STAT5 proteins, showing synergistic effects of STAP-1 inhibition and BCR-ABL or JAK2 tyrosine kinase inhibition. Our results identified STAP-1 as a regulator of CML LSCs and suggested it to be a potential therapeutic target for CML.