title: AMPK inhibition enhances apoptosis in MLL-rearranged pediatric B-acute lymphoblastic leukemia cells.
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.
authors.affiliation: Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padua, Italy. benedetta.accordi@unipd.it
authors.forename: B
authors.initials: B
authors.lastname: Accordi
authors.forename: L
authors.initials: L
authors.lastname: Galla
authors.forename: G
authors.initials: G
authors.lastname: Milani
authors.forename: M
authors.initials: M
authors.lastname: Curtarello
authors.forename: V
authors.initials: V
authors.lastname: Serafin
authors.forename: V
authors.initials: V
authors.lastname: Lissandron
authors.forename: G
authors.initials: G
authors.lastname: Viola
authors.forename: G
authors.initials: G
authors.lastname: te Kronnie
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: L A
authors.initials: LA
authors.lastname: Liotta
authors.forename: S
authors.initials: S
authors.lastname: Indraccolo
authors.forename: G
authors.initials: G
authors.lastname: Basso
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C497422:KMT2A protein, human; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D055372:AMP-Activated Protein Kinases