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Molecular Targets for Therapy

AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells

Leukemia volume 27, pages 1019–1027 (2013)Cite this article

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Abstract

The serine/threonine kinase AMP-activated protein kinase (AMPK) and its downstream effectors, including endothelial nitric oxide synthase and BCL-2, are hyperactivated in B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) cells with MLL gene rearrangements. We investigated the role of activated AMPK in supporting leukemic cell survival and evaluated AMPK as a potential drug target. Exposure of leukemic cells to the commercial AMPK inhibitor compound C resulted in massive apoptosis only in cells with MLL gene rearrangements. These results were confirmed by targeting AMPK with specific short hairpin RNAs. Compound C-induced apoptosis was associated with mitochondrial membrane depolarization, reactive oxygen species production, cytochrome c release and caspases cleavage, indicating intrinsic apoptosis pathway activation. Treatment with low concentrations of compound C resulted in a strong antileukemic activity, together with cytochrome c release and cleavage of caspases and poly(ADP-ribose) polymerase, also in MLL-rearranged primary BCP-ALL samples. Moreover, AMPK inhibition in MLL-rearranged cell lines synergistically enhanced the antiproliferative effects of vincristine, daunorubicin, cytarabine, dexamethasone and L-asparaginase in most of the evaluated conditions. Taken together, these results indicate that the activation of the AMPK pathway directly contributes to the survival of MLL-rearranged BCP-ALL cells and AMPK inhibitors could represent a new therapeutic strategy for this high-risk leukemia.

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Acknowledgements

We thank Dr E Giarin for helping us with the BioBank and Dr R Bortolozzi for figures editing. We are also grateful to Professor D Campana for providing MSCs and constructive comments on the manuscript. This work was supported by grants from the Istituto Superiore di Sanità (Italy/USA program), the Fondazione Città della Speranza, the Associazione Italiana per la Ricerca sul Cancro, the Ministero della Salute (Ricerca Finalizzata 2006—Programma Integrato Oncologia) to GB. Progetto d'Ateneo—Bando 2010 to S.I. and Progetto d'Eccellenza Fondazione CARIPARO to SI and G. teK.

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Authors and Affiliations

  1. Department of Woman and Child Health, Oncohematology Laboratory, University of Padova, Padova, Italy

    B Accordi, L Galla, G Milani, V Serafin, V Lissandron, G Viola, G te Kronnie & G Basso

  2. Immunology and Diagnostic Molecular Oncology, Istituto Oncologico Veneto IRCCS, Padova, Italy

    M Curtarello & S Indraccolo

  3. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy

    R De Maria

  4. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA

    E F Petricoin 3rd & L A Liotta

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  1. B Accordi
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Correspondence to B Accordi.

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BA, LL, EP, and GB are co-inventors on pending patent applications that cover findings within this paper and the authors could receive royalties as a consequence. These applications have been licensed to Theranostics Health, Inc., and LL and EP are equity shareholders. The other authors declare no competing financial interests.

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Accordi, B., Galla, L., Milani, G. et al. AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells. Leukemia 27, 1019–1027 (2013). https://doi.org/10.1038/leu.2012.338

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