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

Ruggero De Maria Marchiano, B. Accordi, L. Galla, G. Milani, M. Curtarello, V. Serafin, V. Lissandron, G. Viola, G. Te Kronnie, E. F. Petricoin, L. A. Liotta, S. Indraccolo, G. Basso

Risultato della ricerca: Contributo in rivistaArticolo in rivista

30 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)1019-1027
Numero di pagine9
RivistaLeukemia
DOI
Stato di pubblicazionePubblicato - 2013

Keywords

  • AMPK
  • MLL rearrangements
  • acute lymphoblastic leukemia
  • apoptosis

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