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

AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells / Accordi, B.; Galla, L.; Milani, G.; Curtarello, M.; Serafin, V.; Lissandron, V.; Viola, G.; Te Kronnie, G.; De Maria, R.; Petricoin, E. F.; Liotta, L. A.; Stefano, Indraccolo; Basso, G.. - In: LEUKEMIA. - ISSN 0887-6924. - 27:5(2013), pp. 1019-1027. [10.1038/leu.2012.338]

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

Serafin, V.;Indraccolo, S.;
2013

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
2013
21-nov-2012
27
5
1019
1027
AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells / Accordi, B.; Galla, L.; Milani, G.; Curtarello, M.; Serafin, V.; Lissandron, V.; Viola, G.; Te Kronnie, G.; De Maria, R.; Petricoin, E. F.; Liotta, L. A.; Stefano, Indraccolo; Basso, G.. - In: LEUKEMIA. - ISSN 0887-6924. - 27:5(2013), pp. 1019-1027. [10.1038/leu.2012.338]
Accordi, B.; Galla, L.; Milani, G.; Curtarello, M.; Serafin, V.; Lissandron, V.; Viola, G.; Te Kronnie, G.; De Maria, R.; Petricoin, E. F.; Liotta, L. A.; Stefano, Indraccolo; Basso, G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1317560
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