publication . Article . 2018

DPP8/9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia

Johnson, Darren C.; Taabazuing, Cornelius Y.; Okondo, Marian C.; Chui, Ashley J.; Rao, Sahana D.; Brown, Fiona C.; Reed, Casie; Peguero, Elizabeth; de Stanchina, Elisa; Kentsis, Alex; ...
Open Access English
  • Published: 01 Jul 2018 Journal: Nature medicine, volume 24, issue 8, pages 1,151-1,156 (issn: 1078-8956, eissn: 1546-170X, Copyright policy)
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 large majority of human acute myeloid le...
Subjects
Medical Subject Headings: hemic and lymphatic diseases
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NIH| Tri-Institutional PhD Program in Chemical Biology
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 1T32GM115327-01
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
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NIH| Characterizing the Mechanism of DPP8/9 Inhibitor-Induced Pyroptosis
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01AI137168-01
  • Funding stream: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
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NIH| Phosphoproteomic signatures for early detection and stratification of AML
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  • Funding stream: NATIONAL CANCER INSTITUTE
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NIH| Aberrant signaling in acute myeloid leukemia
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  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01CA204396-03
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NIH| MOUSE GENETICS
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37 references, page 1 of 3

Okondo, MC. DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis. Nat Chem Biol. 2017; 13: 46-53 [OpenAIRE] [PubMed]

Taabazuing, CY, Okondo, MC, Bachovchin, DA. Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages. Cell Chem Biol. 2017; 24: e504-514 [OpenAIRE] [PubMed]

Okondo, MC. Inhibition of Dpp8/9 Activates the Nlrp1b Inflammasome. Cell Chem Biol. 2018 [OpenAIRE]

Zhang, H, Chen, Y, Keane, FM, Gorrell, MD. Advances in understanding the expression and function of dipeptidyl peptidase 8 and 9. Mol Cancer Res. 2013; 11: 1487-1496 [PubMed]

Rosenblum, JS, Kozarich, JW. Prolyl peptidases: a serine protease subfamily with high potential for drug discovery. Curr Opin Chem Biol. 2003; 7: 496-504 [OpenAIRE] [PubMed]

Wagner, L, Klemann, C, Stephan, M, von Horsten, S. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin Exp Immunol. 2016; 184: 265-283 [OpenAIRE] [PubMed]

Adams, S. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004; 64: 5471-5480 [PubMed]

Walsh, MP. Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors. PLoS One. 2013; 8: e58860 [OpenAIRE] [PubMed]

Cunningham, CC. Talabostat. Expert Opin Investig Drugs. 2007; 16: 1459-1465

Eager, RM. Phase II trial of talabostat and docetaxel in advanced non-small cell lung cancer. Clin Oncol (R Coll Radiol). 2009; 21: 464-472 [OpenAIRE] [PubMed]

Eager, RM. Phase II assessment of talabostat and cisplatin in second-line stage IV melanoma. BMC Cancer. 2009; 9: 263 [OpenAIRE] [PubMed]

Lankas, GR. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes. 2005; 54: 2988-2994 [PubMed]

Jiaang, WT. Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8. Bioorg Med Chem Lett. 2005; 15: 687-691 [PubMed]

Wu, JJ. Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor. Biochem Pharmacol. 2009; 78: 203-210 [PubMed]

Bachovchin, DA. A high-throughput, multiplexed assay for superfamily-wide profiling of enzyme activity. Nat Chem Biol. 2014; 10: 656-663 [OpenAIRE] [PubMed]

37 references, page 1 of 3
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