DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia

Nat Med. 2018 Aug;24(8):1151-1156. doi: 10.1038/s41591-018-0082-y.

Darren C Johnson ¹, Cornelius Y Taabazuing ², Marian C Okondo ², Ashley J Chui ¹, Sahana D Rao ¹, Fiona C Brown ³, Casie Reed ³, Elizabeth Peguero ⁴, Elisa de Stanchina ⁴, Alex Kentsis ¹ ³ ⁵ ⁶, Daniel A Bachovchin ⁷ ⁸ ⁹

Affiliations

1 Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4 Antitumor Assessment Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6 Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7 Tri-institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. bachovcd@mskcc.org.
8 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. bachovcd@mskcc.org.
9 Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. bachovcd@mskcc.org.

PMID: 29967349 DOI: 10.1038/s41591-018-0082-y

Abstract

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 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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