Hyperactive Natural Killer cells in Rag2 knockout mice inhibit the development of acute myeloid leukemia
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Published:2023-12-21
Issue:1
Volume:6
Page:
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ISSN:2399-3642
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Container-title:Communications Biology
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language:en
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Short-container-title:Commun Biol
Author:
Sugimoto Emi, Li Jingmei, Hayashi Yasutaka, Iida Kohei, Asada ShuheiORCID, Fukushima Tsuyoshi, Tamura Moe, Shikata Shiori, Zhang Wenyu, Yamamoto Keita, Kawabata Kimihito Cojin, Kawase Tatsuya, Saito Takeshi, Yoshida Taku, Yamazaki SatoshiORCID, Kaito Yuta, Imai Yoichi, Denda Tamami, Ota Yasunori, Fukuyama TomofusaORCID, Tanaka YosukeORCID, Enomoto Yutaka, Kitamura ToshioORCID, Goyama SusumuORCID
Abstract
AbstractImmunotherapy has attracted considerable attention as a therapeutic strategy for cancers including acute myeloid leukemia (AML). In this study, we found that the development of several aggressive subtypes of AML is slower in Rag2−/− mice despite the lack of B and T lymphocytes, even compared to the immunologically normal C57BL/6 mice. Furthermore, an orally active p53-activating drug shows stronger antileukemia effect on AML in Rag2−/− mice than C57BL/6 mice. Intriguingly, Natural Killer (NK) cells in Rag2−/− mice are increased in number, highly express activation markers, and show increased cytotoxicity to leukemia cells in a coculture assay. B2m depletion that triggers missing-self recognition of NK cells impairs the growth of AML cells in vivo. In contrast, NK cell depletion accelerates AML progression in Rag2−/− mice. Interestingly, immunogenicity of AML keeps changing during tumor evolution, showing a trend that the aggressive AMLs generate through serial transplantations are susceptible to NK cell-mediated tumor suppression in Rag2−/− mice. Thus, we show the critical role of NK cells in suppressing the development of certain subtypes of AML using Rag2−/− mice, which lack functional lymphocytes but have hyperactive NK cells.
Funder
MEXT | Japan Society for the Promotion of Science Japan Agency for Medical Research and Development
Publisher
Springer Science and Business Media LLC
Subject
General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)
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