Journal
NATURE MEDICINE
Volume 24, Issue 8, Pages 1151-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0082-y
Keywords
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Funding
- Josie Robertson Foundation
- Stand Up to Cancer-Innovative Research Grant (American Association for Cancer Research, the scientific partner of SU2C) [SU2C-AACR-IRG11-17]
- Pew Charitable Trusts
- NIH [R01 AI137168, R21 CA188881, R01 CA204396, T32 GM115327]
- NIH (MSKCC Core Grant) [P30 CA008748]
- American Cancer Society [PF-17-224-01 - CCG]
- Borroughs Wellcome Fund
- Alex's Lemonade Stand Foundation
- Gabrielle's Angel Foundation
- Damon Runyon Cancer Research Foundation
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Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induce a lytic form of cell death called pyroptosis in mouse and human monocytes and macrophages(1,2). In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor NIrp1b, which in turn activates pro-caspase-1 to mediate cell death(3) , but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known. Here we show that the CARD-containing protein CARD8 mediates DPP8/9 inhibitor-induced procaspase-1-dependent pyroptosis in human myeloid cells. We further show that DPP8/9 inhibitors induce pyroptosis in the majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies an activator of CARD8 in human cells and indicates that its activation by small-molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML.
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