title: FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia.
abstract: FLT3 abnormalities are negative prognostic markers in acute leukemia. Infant leukemias are a subgroup with frequent MLL (KMT2A) rearrangements, FLT3 overexpression and high sensitivity to cytarabine, but dismal prognosis. Cytarabine is transported into cells by Human Equilibrative Nucleoside Transporter-1 (hENT1, SLC29A1), but the mechanisms that regulate hENT1 in acute leukemia have been scarcely studied.We explored the expression and functional link between FLT3 and main cytarabine transporters in 50 pediatric patients diagnosed with acute lymphoblastic leukemia and MLL rearrangement (ALL-MLL+) and other subtypes of leukemia, and in leukemia cell lines.A significant positive correlation was found between FLT3 and hENT1 expression in patients. Cytarabine uptake into cells was mediated mainly by hENT1, hENT2 and hCNT1. hENT1-mediated uptake of cytarabine was transiently abolished by the FLT3 inhibitor PKC412, and this effect was associated with decreased hENT1 mRNA and protein levels. Noticeably, the cytotoxicity of cytarabine was lower when cells were first exposed to FLT3 inhibitors (PKC412 or AC220), probably due to decreased hENT1 activity, but we observed a higher cytotoxic effect if FLT3 inhibitors were administered after cytarabine.FLT3 regulates hENT1 activity and thereby affects cytarabine cytotoxicity. The sequence of administration of cytarabine and FLT3 inhibitors is important to maintain their efficacy.
authors.affiliation: Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain.|National Biomedical Research Institute on Rare Diseases (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Català
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine (IBUB), Barcelona, Spain.|Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Marçal
authors.initials: M
authors.lastname: Pastor-Anglada
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine (IBUB), Barcelona, Spain.
authors.forename: Liska
authors.initials: L
authors.lastname: Caviedes-Cárdenas
authors.affiliation: Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Roberta
authors.initials: R
authors.lastname: Malatesta
authors.affiliation: Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain.|National Biomedical Research Institute on Rare Diseases (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Rives
authors.affiliation: Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Vega-García
authors.affiliation: National Biomedical Research Institute on Rare Diseases (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain.|Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Camós
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine (IBUB), Barcelona, Spain.|Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain.|Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Fernández-Calotti
mesh_terms: D000293:Adolescent; D017209:Apoptosis; D001692:Biological Transport; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000378:metabolism*; D004252:DNA Mutational Analysis; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D033722:Equilibrative-Nucleoside Transporter 2 / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D033703:Nucleoside Transport Proteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D033722:Equilibrative-Nucleoside Transporter 2; C497422:KMT2A protein, human; D033703:Nucleoside Transport Proteins; C438649:SLC29A1 protein, human; C438654:SLC29A2 protein, human; C501424:SLC29A3 protein, human; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019311:Staurosporine; C059539:midostaurin
keywords: FLT3; cytarabine; hENT1; nucleoside transporters; pediatric acute leukemia