FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia
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Albert Català1,2,6, Marçal Pastor-Anglada3,4,6, Liska Caviedes-Cárdenas3, Roberta Malatesta5, Susana Rives1,2,6, Nerea Vega-García5, Mireia Camós2,5,6,*, Paula Fernández-Calotti3,4,6,*
1Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain
2National Biomedical Research Institute on Rare Diseases (CIBER ER), Instituto de Salud Carlos III, Madrid, Spain
3Department of Biochemistry and Molecular Biology, University of Barcelona, Institute of Biomedicine (IBUB), Barcelona, Spain
4Oncology Program, National Biomedical Research Institute of Liver and Gastrointestinal Diseases (CIBER EHD), Instituto de Salud Carlos III, Madrid, Spain
5Hematology Laboratory, Hospital Sant Joan de Déu, University of Barcelona, Esplugues de Llobregat, Barcelona, Spain
6Institut de Recerca Pediàtrica Hospital Sant Joan de Déu (IRP-HSJD), Esplugues de Llobregat, Barcelona, Spain
Albert Català, email: email@example.com
Marçal Pastor-Anglada, email: firstname.lastname@example.org
Keywords: FLT3, Cytarabine, hENT1, nucleoside transporters, pediatric acute leukemia
Received: November 04, 2015 Accepted: June 26, 2016 Published: July 06, 2016
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.
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