Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents.

Bing Z. Carter, Po Yee Mak, Duncan H. Mak, Yuexi Shi, Yihua Qiu, James M. Bogenberger, Hong Mu, Raoul Tibes, Hui Yao, Kevin R. Coombes, Rodrigo O. Jacamo, Teresa McQueen, Steven M. Kornblau, Michael Andreeff

Research output: Chapter in Book/Report/Conference proceedingChapter

42 Citations (Scopus)

Abstract

Acute myeloid leukemia (AML) therapy has limited long-term efficacy because patients frequently develop disease relapse because of the inability of standard chemotherapeutic agents to target AML stem/progenitor cells. Here, we identify deregulated apoptotic components in AML stem/progenitor cells and investigate the individual and combinatorial effects of the novel inhibitor of apoptosis (IAP) protein antagonist and second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant and demethylating epigenetic modulators. Protein expression was measured by reversed-phase protein array in AML patient (n = 511) and normal (n = 21) samples and by western blot in drug-treated cells. The antileukemic activity of birinapant and demethylating agents was assessed in vitro and in an in vivo AML mouse xenograft model (n = 10 mice per group). All statistical tests were two-sided. Compared with bulk AML cells, CD34(+)38(-) AML stem/progenitors expressed increased cIAP1 and caspase-8 levels and decreased SMAC levels (one-way analysis of variance followed by Tukey's multiple comparison test, P < .001). Birinapant induced death receptor-/caspase-8-mediated apoptosis in AML cells, including in AML stem/progenitor cells, but not in normal CD34(+) cells. Demethylating agents modulated extrinsic apoptosis pathway components and, when combined with birinapant, were highly synergistic in vitro (combination index < 1), and also more effective in vivo (P < .001, by Student t test, for the median survival of birinapant plus 5-azacytadine vs birinapant alone or vs controls). cIAP1, SMAC, and caspase-8 appear to play a role in AML stem cell survival, and synergistic targeting of these cells with birinapant and demethylating agents shows potential utility in leukemia therapy.

Original languageEnglish (US)
Title of host publicationJournal of the National Cancer Institute
Volume106
Edition2
DOIs
StatePublished - 2014
Externally publishedYes

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Acute Myeloid Leukemia
Stem Cells
Apoptosis
Caspase 8
Caspases
Myeloid Cells
birinapant
Inhibitor of Apoptosis Proteins
Myeloid Progenitor Cells
Protein Array Analysis
Death Domain Receptors
Heterografts
Epigenomics
Cell Survival
Analysis of Variance
Leukemia
Western Blotting
Students
Recurrence
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carter, B. Z., Mak, P. Y., Mak, D. H., Shi, Y., Qiu, Y., Bogenberger, J. M., ... Andreeff, M. (2014). Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. In Journal of the National Cancer Institute (2 ed., Vol. 106) https://doi.org/10.1093/jnci/djt440

Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. / Carter, Bing Z.; Mak, Po Yee; Mak, Duncan H.; Shi, Yuexi; Qiu, Yihua; Bogenberger, James M.; Mu, Hong; Tibes, Raoul; Yao, Hui; Coombes, Kevin R.; Jacamo, Rodrigo O.; McQueen, Teresa; Kornblau, Steven M.; Andreeff, Michael.

Journal of the National Cancer Institute. Vol. 106 2. ed. 2014.

Research output: Chapter in Book/Report/Conference proceedingChapter

Carter, BZ, Mak, PY, Mak, DH, Shi, Y, Qiu, Y, Bogenberger, JM, Mu, H, Tibes, R, Yao, H, Coombes, KR, Jacamo, RO, McQueen, T, Kornblau, SM & Andreeff, M 2014, Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. in Journal of the National Cancer Institute. 2 edn, vol. 106. https://doi.org/10.1093/jnci/djt440
Carter BZ, Mak PY, Mak DH, Shi Y, Qiu Y, Bogenberger JM et al. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. In Journal of the National Cancer Institute. 2 ed. Vol. 106. 2014 https://doi.org/10.1093/jnci/djt440
Carter, Bing Z. ; Mak, Po Yee ; Mak, Duncan H. ; Shi, Yuexi ; Qiu, Yihua ; Bogenberger, James M. ; Mu, Hong ; Tibes, Raoul ; Yao, Hui ; Coombes, Kevin R. ; Jacamo, Rodrigo O. ; McQueen, Teresa ; Kornblau, Steven M. ; Andreeff, Michael. / Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. Journal of the National Cancer Institute. Vol. 106 2. ed. 2014.
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AU - Bogenberger, James M.

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