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

C. Grimaldi, F. Chiarini, G. Tabellini, F. Ricci, P. L. Tazzari, M. Battistelli, E. Falcieri, R. Bortul, F. Melchionda, I. Iacobucci, P. Pagliaro, G. Martinelli, A. Pession, J. T. Barata, J. A. McCubrey, A. M. Martelli

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)91-100
Number of pages10
JournalLeukemia
Volume26
Issue number1
DOIs
Publication statusPublished - Jan 2012

Keywords

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

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    Grimaldi, C., Chiarini, F., Tabellini, G., Ricci, F., Tazzari, P. L., Battistelli, M., Falcieri, E., Bortul, R., Melchionda, F., Iacobucci, I., Pagliaro, P., Martinelli, G., Pession, A., Barata, J. T., McCubrey, J. A., & Martelli, A. M. (2012). AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: Therapeutic implications. Leukemia, 26(1), 91-100. https://doi.org/10.1038/leu.2011.269