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

被引：293

作者：

Johnson, Darren C. ^{[1
]}

Taabazuing, Cornelius Y. ^{[2
]}

Okondo, Marian C. ^{[2
]}

Chui, Ashley J. ^{[1
]}

Rao, Sahana D. ^{[1
]}

Brown, Fiona C. ^{[3
]}

Reed, Casie ^{[3
]}

Peguero, Elizabeth ^{[4
]}

de Stanchina, Elisa ^{[4
]}

Kentsis, Alex ^{[1
,3
,5
,6
]}

Bachovchin, Daniel A. ^{[1
,2
,6
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Triinst PhD Program Chem Biol, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Chem Biol Program, 1275 York Ave, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Facil, 1275 York Ave, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Pediat, 1275 York Ave, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Pharmacol Program, Weill Cornell Grad Sch Med Sci, 1275 York Ave, New York, NY 10021 USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 08期

关键词：

DIPEPTIDYL PEPTIDASE-IV; CASPASE-1; AUTOPROTEOLYSIS; POTENT; INFLAMMASOME; CANCER; HEMATOPOIESIS; ISOINDOLINE; TALABOSTAT; EXPRESSION; APOPTOSIS;

D O I：

10.1038/s41591-018-0082-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1151 / +

页数：8

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