Acute myeloid leukemia (AML) carries a 10–100 fold lower mutational burden than other neoplastic entities. Mechanistic explanations for why a low number of mutations suffice to induce leukemogenesis are therefore required. Here we demonstrate that transgenic overexpression of the wild type sphingosine-1-phosphate receptor 3 (S1P3) in murine hematopoietic stem cells is sufficient to induce a transplantable myeloid leukemia. In contrast, S1P3 expression in more mature compartments does not cause malignant transformation. Treatment with the sphingosine phosphate receptor modulator Fingolimod, which prevents receptor signaling, normalized peripheral blood cell counts and reduced spleen sizes in S1P3 expressing mice. Gene expression analyses in AML patients revealed elevated S1P3 expression specifically in two molecular subclasses. Our data suggest a previously unrecognized contribution of wild type S1P3 signaling to leukemogenesis that warrants the exploration of S1P3 antagonists in preclinical AML models.
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The authors gratefully acknowledge expert technical support by Martina de Groot as well as by the animal care facility, especially Natalie Krause. This work was supported by grants from the National Cancer Institute (1 PO1 CA108671 to H.L.P), the Deutsche Forschungsgemeinschaft (Pa 611/9–1 to H.L.P. and Ju 3104/1–1 to J.S.J. within the research consortium FOR 2674, MU1328/14–1 and MU1328/15–1 to C.M.T. and NO 406/3-1 to J.-R.N.), the Deutsche Krebshilfe (70112974 and 110500 to C.M.T.), the José-Carreras-Stiftung (DJCLS R13/04 and DJCLS 22R/2017 to C.M.T.), the Italian Ministry of Education, Universities and Research (IDEAS RBID08777T to J.-R.N. and M.S.) and the Italian Ministry of Health (GR-2011-02346974 to F.P.) S.V. was funded by the “MOTI-VATE” scholarship program supported by the Else-Kroener-Fresenius-Stiftung.
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Vorbach, S., Gründer, A., Zhou, F. et al. Enhanced expression of the sphingosine-1-phosphate-receptor-3 causes acute myelogenous leukemia in mice. Leukemia 34, 721–734 (2020). https://doi.org/10.1038/s41375-019-0577-7