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

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

Authors:	Johnson, D. C.; Taabazuing, C. Y.; Okondo, M. C.; Chui, A. J.; Rao, S. D.; Brown, F. C.; Reed, C.; Peguero, E.; de Stanchina, E.; Kentsis, A.; Bachovchin, D. A.
Article Title:	DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia
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 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. © 2018, The Author(s).
Journal Title:	Nature Medicine
Volume:	24
Issue:	8
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Date Published:	2018-08-01
Start Page:	1151
End Page:	1156
Language:	English
DOI:	10.1038/s41591-018-0082-y
PROVIDER:	scopus
PMCID:	PMC6082709
PUBMED:	29967349
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85049580710&doi=10.1038%2fs41591-018-0082-y&partnerID=40&md5=2e867541415c535a2262b06de6bad1c9
Notes:	Letter -- Export Date: 1 October 2018 -- Source: Scopus