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Molecular Targets for Therapy

Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential

Leukemia volume 28, pages 739–748 (2014)Cite this article

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Abstract

B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

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Acknowledgements

This work was supported by grants from MinSan 2008 ‘Molecular therapy in pediatric sarcomas and leukemias against IGF-IR system: new drugs, best drug–drug interactions, mechanisms of resistance and indicators of efficacy’ (to AMM), MIUR PRIN 200938XJLA_003 (to SC) and MIUR FIRB 2010 (RBAP10447J_003 to AMM and RBAP10Z7FS_002 to SC).

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  1. L M Neri and A Cani: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

    L M Neri, A Cani, C Simioni & S Capitani

  2. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    A M Martelli

  3. Institute of Molecular Genetics, National Research Council, Pavia, Italy

    A M Martelli

  4. Division of Medicine, Department of Hematology/Oncology/Palliative Medicine, University of Rostock, Rostock, Germany

    C Junghanss

  5. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    G Tabellini

  6. Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy

    F Ricci, P L Tazzari & P Pagliaro

  7. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA

    J A McCubrey

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  1. L M Neri
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Neri, L., Cani, A., Martelli, A. et al. Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia 28, 739–748 (2014). https://doi.org/10.1038/leu.2013.226

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