中国医学科学院黄波研究组、北京大学人民医院张晓辉和郑州大学第一附属医院张毅研究组合作发现，肿瘤细胞释放的犬尿氨酸(Kyn)通过激活芳烃受体-Runt相关转录因子1 (AhR-RUNX1)使MEP向巨核细胞分化。这一研究成果发表在2023年11月2日出版的国际学术期刊《自然—免疫学》上。

他们发现肿瘤细胞释放的Kyn通过激活AhR-RUNX1轴，使巨核细胞-红细胞祖细胞(MEP)在癌症个体中向巨核细胞分化。在肿瘤生长过程中，来自肿瘤细胞的大量Kyn被释放到外周，在那里它们通过转运体SLC7A8被MEP吸收。在细胞质中，Kyn与AhR结合并激活AhR，导致其易位进入细胞核，在细胞核中AhR转激活RUNX1，从而调节MEP向巨核细胞的分化。此外，激活的AhR上调MEPs中的SLC7A8，诱导正反馈。

重要的是，Kyn–AhR–RUNX1调节的MEP分化在人源化小鼠和癌症个体中都得到证实，这为预防血小板增加和红细胞减少提供了潜在的策略。

研究人员表示，肿瘤衍生因子被认为调节癌症患者的血小板增多和红细胞减少;然而，这些因素尚未被确定。

附：英文原文

Title: Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR–RUNX1

Author: Zhou, Li, Wu, Dongxiao, Zhou, Yabo, Wang, Dianheng, Fu, Haixia, Huang, Qiusha, Qin, Guohui, Chen, Jie, Lv, Jiadi, Lai, Shaoyang, Zhang, Huafeng, Tang, Ke, Ma, Jingwei, Fiskesund, Roland, Zhang, Yi, Zhang, Xiaohui, Huang, Bo

Issue&Volume: 2023-11-02

Abstract: Tumor-derived factors are thought to regulate thrombocytosis and erythrocytopenia in individuals with cancer; however, such factors have not yet been identified. Here we show that tumor cell-released kynurenine (Kyn) biases megakaryocytic–erythroid progenitor cell (MEP) differentiation into megakaryocytes in individuals with cancer by activating the aryl hydrocarbon receptor–Runt-related transcription factor 1 (AhR–RUNX1) axis. During tumor growth, large amounts of Kyn from tumor cells are released into the periphery, where they are taken up by MEPs via the transporter SLC7A8. In the cytosol, Kyn binds to and activates AhR, leading to its translocation into the nucleus where AhR transactivates RUNX1, thus regulating MEP differentiation into megakaryocytes. In addition, activated AhR upregulates SLC7A8 in MEPs to induce positive feedback. Importantly, Kyn–AhR–RUNX1-regulated MEP differentiation was demonstrated in both humanized mice and individuals with cancer, providing potential strategies for the prevention of thrombocytosis and erythrocytopenia.

DOI: 10.1038/s41590-023-01662-3

Source: https://www.nature.com/articles/s41590-023-01662-3