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 down-modulated 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.

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications / Grimaldi, Cecilia; Chiarini, Francesca; Tabellini, G.; Ricci, F.; Tazzari, P. L.; Battistelli, M.; Falcieri, E.; Bortul, R.; Melchionda, F.; Iacobucci, Ilaria; Pagliaro, P.; Martinelli, Giovanni; Pession, Andrea; Barata, J. T.; Mccubrey, J. A.; Martelli, ALBERTO MARIA. - In: LEUKEMIA. - ISSN 0887-6924. - 26:(2012), pp. 91-100. [10.1038/leu.2011.269]

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

CHIARINI, FRANCESCA;
2012

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 down-modulated 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.
2012
26
91
100
AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications / Grimaldi, Cecilia; Chiarini, Francesca; Tabellini, G.; Ricci, F.; Tazzari, P. L.; Battistelli, M.; Falcieri, E.; Bortul, R.; Melchionda, F.; Iacobucci, Ilaria; Pagliaro, P.; Martinelli, Giovanni; Pession, Andrea; Barata, J. T.; Mccubrey, J. A.; Martelli, ALBERTO MARIA. - In: LEUKEMIA. - ISSN 0887-6924. - 26:(2012), pp. 91-100. [10.1038/leu.2011.269]
Grimaldi, Cecilia; Chiarini, Francesca; Tabellini, G.; Ricci, F.; Tazzari, P. L.; Battistelli, M.; Falcieri, E.; Bortul, R.; Melchionda, F.; Iacobucci, Ilaria; Pagliaro, P.; Martinelli, Giovanni; Pession, Andrea; Barata, J. T.; Mccubrey, J. A.; Martelli, ALBERTO MARIA
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1288383
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