title: The synergism of MCL1 and glycolysis on pediatric acute lymphoblastic leukemia cell survival and prednisolone resistance.
abstract: In vitro and in vivo resistance to prednisolone are predictive for an adverse prognosis in pediatric precursor B-acute lymphoblastic leukemia. Causes of resistance are still poorly understood. In this study, we observed that prednisolone exposure of prednisolone-sensitive patients' leukemic cells decreased anti-apoptotic MCL1 protein levels by 2.9-fold, while MCL1 protein expression in prednisolone-resistant leukemic patients' cells was unaffected (P<0.01). Locked nucleic acid oligonucleotides directed against MCL1 reduced MCL1 protein levels by 82±16% (P<0.05) in leukemic cells, decreased proliferation by 9-fold and sensitized to prednisolone up to 80.8-fold, compared to a non-silencing-control locked nucleic acid (P<0.05). Remarkably, we discovered that MCL1-silencing up-regulated the glucose consumption of leukemic cells by 2.5-fold (P<0.05), suggesting a potential rescue mechanism mediated by glycolysis. Targeting glycolysis by 2-deoxyglucose synergistically inhibited leukemic survival by 23.2-fold in MCL1-silenced cells (P<0.05). Moreover, 2-deoxyglucose and MCL1 locked nucleic acid concomitantly sensitized leukemic cells to prednisolone compared to MCL1 locked nucleic acid or 2-deoxyglucose alone (P<0.05). In conclusion, these results indicate the need to target both MCL1 and glycolysis simultaneously to inhibit leukemic survival and sensitize acute leukemia patients towards prednisolone.
authors.affiliation: m.l.denboer@erasmusmc.nl.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Ariës
authors.forename: Bo R
authors.initials: BR
authors.lastname: Hansen
authors.forename: Troels
authors.initials: T
authors.lastname: Koch
authors.forename: Rosanna
authors.initials: R
authors.lastname: van den Dungen
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011239:Prednisolone