title: Antileukemic Activity of 2-Deoxy-d-Glucose through Inhibition of N-Linked Glycosylation in Acute Myeloid Leukemia with FLT3-ITD or c-KIT Mutations.
abstract: We assessed the antileukemic activity of 2-deoxy-d-glucose (2-DG) through the modulation of expression of receptor tyrosine kinases (RTK) commonly mutated in acute myeloid leukemia (AML). We used human leukemic cell lines cells, both in vitro and in vivo, as well as leukemic samples from AML patients to demonstrate the role of 2-DG in tumor cell growth inhibition. 2-DG, through N-linked glycosylation inhibition, affected the cell-surface expression and cellular signaling of both FTL3-ITD and mutated c-KIT and induced apoptotic cell death. Leukemic cells harboring these mutated RTKs (MV4-11, MOLM-14, Kasumi-1, and TF-1 c-KIT D816V) were the most sensitive to 2-DG treatment in vitro as compared with nonmutated cells. 2-DG activity was also demonstrated in leukemic cells harboring FLT3-TKD mutations resistant to the tyrosine kinase inhibitor (TKI) quizartinib. Moreover, the antileukemic activity of 2-DG was particularly marked in c-KIT-mutated cell lines and cell samples from core binding factor-AML patients. In these cells, 2-DG inhibited the cell-surface expression of c-KIT, abrogated STAT3 and MAPK-ERK pathways, and strongly downregulated the expression of the receptor resulting in a strong in vivo effect in NOD/SCID mice xenografted with Kasumi-1 cells. Finally, we showed that 2-DG decreases Mcl-1 protein expression in AML cells and induces sensitization to both the BH3 mimetic inhibitor of Bcl-xL, Bcl-2 and Bcl-w, ABT-737, and cytarabine. In conclusion, 2-DG displays a significant antileukemic activity in AML with FLT3-ITD or KIT mutations, opening a new therapeutic window in a subset of AML with mutated RTKs.
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Larrue
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Saland
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France. Laboratoire d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.
authors.forename: François
authors.initials: F
authors.lastname: Vergez
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Nizar
authors.initials: N
authors.lastname: Serhan
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France. Laboratoire d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France. Laboratoire d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mansat-De Mas
authors.affiliation: Institut Cochin, Département Développement, Reproduction, Cancer, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France. Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Hospital
authors.affiliation: Institut Cochin, Département Développement, Reproduction, Cancer, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France. Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Tamburini
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Manenti
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France.
authors.forename: Jean Emmanuel
authors.initials: JE
authors.lastname: Sarry
authors.affiliation: Cancer Research Center of Toulouse (CRCT), UMR1037 INSERM, ERL5294 CNRS, Toulouse, France. Université Toulouse III Paul Sabatier, Toulouse, France. Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France. recher.christian@iuct-oncopole.fr.
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D052160:Benzothiazoles / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003561:Cytarabine / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006019:Glycolysis; D006031:Glycosylation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010671:Phenylurea Compounds; D010879:Piperazines; D013449:Sulfonamides; D003561:Cytarabine; C544967:quizartinib; D003847:Deoxyglucose; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3