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 macrophages1,2. In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death3, 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 pro-caspase-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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We thank S. Monette for histology advice, and W. Bachovchin, W. Wu and J. Lai (Tufts University, USA) for Val-boroPro, 1G244, 8j and l-allo-Ile-isoindoline. This work was supported by the Josie Robertson Foundation (D.A.B. and A.K.), a Stand Up to Cancer-Innovative Research Grant (grant number SU2C-AACR-IRG11-17 to D.A.B.; Stand Up to Cancer is a program of the Entertainment Industry Foundation; research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C), the Pew Charitable Trusts (D.A.B. is a Pew-Stewart Scholar in Cancer Research), the NIH (R01 AI137168 to D.A.B.; R21 CA188881 and R01 CA204396 to A.K.; T32 GM115327-Tan to D.C.J.; the MSKCC Core Grant P30 CA008748), the American Cancer Society (Postdoctoral Fellowship PF-17-224-01 – CCG to C.Y.T.), Borroughs Wellcome Fund (A.K.), Alex’s Lemonade Stand Foundation (A.K.), Gabrielle’s Angel Foundation (A.K.) and the Damon Runyon Cancer Research Foundation (A.K. is the Damon Runyon-Richard Lumsden Foundation Clinical Investigator).
The authors declare no competing interests.
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Johnson, D.C., Taabazuing, C.Y., Okondo, M.C. et al. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med 24, 1151–1156 (2018). https://doi.org/10.1038/s41591-018-0082-y
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