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  • Molecular Targets For Therapy (MTT)
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Molecular Targets for Therapy (MTT)

Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia

Leukemia volume 17, pages 2081–2089 (2003)Cite this article

Abstract

XIAP is a member of the inhibitors-of-apoptosis family of proteins, which inhibit caspases and block cell death, with prognostic importance in AML. Here we demonstrate that cytokines regulate the expression of XIAP in leukemic cell lines and primary AML blasts. Inhibition of phosphatidylinositol-3 kinase (PI3K) with LY294002 and of the mitogen-activated protein kinase (MAPK) cascade by PD98059 resulted in decreased XIAP levels (34±8.7 and 23±5.7%, respectively). We then generated OCI-AML3 cells with constitutively phosphorylated Akt (p473-Akt) by retroviral gene transfer. Neither these nor Akt inhibitor-treated OCI-AML3 cells showed changes in XIAP levels, suggesting that XIAP expression is regulated by PI3K downstream effectors other than Akt. The induction of XIAP expression by cytokines through PI3K/MAPK pathways is consistent with its role in cell survival. Exposure of leukemic cells to chemotherapeutic agents decreased XIAP protein levels by caspase-dependent XIAP cleavage. Targeting XIAP by XIAP antisense oligonucleotide resulted in downregulation of XIAP, activation of caspases and cell death, and sensitized HL-60 cells to Ara-C. Our results suggest that XIAP is regulated by cytokines through PI3K, and to a lesser degree through MAPK pathways. Selective downregulation of XIAP expression might be of therapeutic benefit to leukemic patients.

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Acknowledgements

We thank Rosemarie Lauzon for her assistance in preparing the manuscript. This work was supported in part by Grants PO1 CA55164, PO1 CA16672, PO1 CA49639, and CA51025. We also thank Patty Contreras (Idun Pharmaceuticals, La Jolla, CA, USA) for supplying us with caspase inhibitors.

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Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B Z Carter, M Milella, T Tsao, T McQueen, W D Schober, W Hu & M Andreeff

  2. East Carolina University, Greenville, NC, USA

    L Steelman & J A McCubrey

  3. Isis Pharmaceuticals, Carlsbad, CA, USA

    N M Dean

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  1. B Z Carter
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  2. M Milella
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Carter, B., Milella, M., Tsao, T. et al. Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia. Leukemia 17, 2081–2089 (2003). https://doi.org/10.1038/sj.leu.2403113

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