FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia
Por:
Català-Temprano A, Pastor-Anglada M, Caviedes-Cárdenas L, Malatesta R, Rives-Solà S, Vega-García N, Camós-Guijosa M and Fernández-Calotti P
Publicada:
2 ago 2016
Ahead of Print:
6 jul 2016
Categoría:
Oncology
Resumen:
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.
Filiaciones:
Català-Temprano A:
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
Pastor-Anglada M:
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
Caviedes-Cárdenas L:
Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine (IBUB), Barcelona, Spain
Malatesta R:
Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain
Rives-Solà S:
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
Vega-García N:
Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain
Camós-Guijosa M:
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
Fernández-Calotti P:
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
Green Submitted, Green Published, gold
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