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Molecular Targets for Therapy

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

Abstract

The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be downmodulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4+ T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34+/CD7/CD4) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL.

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Acknowledgements

This study 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’, MIUR PRIN 2008 (2008THTNLC) and MIUR FIRB 2010 (RBAP10447J_003) to AMM.

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Correspondence to A M Martelli.

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Grimaldi, C., Chiarini, F., Tabellini, G. et al. AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications. Leukemia 26, 91–100 (2012). https://doi.org/10.1038/leu.2011.269

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  • DOI: https://doi.org/10.1038/leu.2011.269

Keywords

  • chemotherapy
  • signal transduction
  • anti-diabetic drug
  • targeted therapy
  • translation

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