Tumor cell-released kynurenine biases MEP differentiation into megakaryocytes in individuals with cancer by activating AhR-RUNX1
Li Zhou 1, Dongxiao Wu 1, Yabo Zhou 1,
Dianheng Wang 1, Haixia Fu 2, Qiusha Huang 2, Guohui Qin 3, Jie Chen 1, Jiadi
Lv 1, Shaoyang Lai 4, Huafeng Zhang 5, Ke Tang 6, Jingwei Ma 7, Roland
Fiskesund 8 9, Yi Zhang 10, Xiaohui Zhang 11, Bo Huang 12 13
Nat Immunol.2023 Nov 2. doi:
10.1038/s41590-023-01662-3.
PMID: 37919525
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.