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Resistance of leukemia cells to cytarabine chemotherapy is mediated by bone marrow stroma, involves cell-surface equilibrative nucleoside transporter-1 removal and correlates with patient outcome

2017; Impact Journals LLC; Volume: 8; Issue: 14 Linguagem: Inglês

10.18632/oncotarget.14981

1949-2553

Patricia Macanas-Pirard, Richard Broekhuizen, Alfonso González, Claudia Oyanadel, Daniël Ernst, Patricia García, Viviana P. Montecinos, Felipe A. Court, Mauricio Ocqueteau, Pablo Ramírez, Bruno Nervi,

Pancreatic and Hepatic Oncology Research

// Patricia Macanas-Pirard 1 , Richard Broekhuizen 1, 7 , Alfonso González 2 , Claudia Oyanadel 3 , Daniel Ernst 1 , Patricia García 4, 7 , Viviana P. Montecinos 1 , Felipe Court 5 , Mauricio Ocqueteau 1 , Pablo Ramirez 6 , Bruno Nervi 1, 7 1 Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile 2 Facultad de Medicina, Universidad San Sebastián, Center for Aging and Regeneration (CARE), Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile 3 Facultad de Ciencia, Universidad San Sebastián, Fundación Ciencia y Vida, Santiago, Chile 4 Department of Pathology, Advanced Center for Chronic Diseases (ACCDiS), UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile 5 Department of Physiology, Millennium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile 6 Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Región de los Ríos, Chile 7 Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile Correspondence to: Bruno Nervi, email: bnervi@med.puc.cl Keywords: leukemia, cytarabine-resistance, ENT1, bone marrow stroma, biomarker Received: May 23, 2016 Accepted: January 06, 2017 Published: February 01, 2017 ABSTRACT The interaction between acute myeloid leukemia cells (AML) with the bone marrow stroma cells (BMSCs) determines a protective environment that favors tumor development and resistance to conventional chemotherapy. We showed that BMSCs secrete soluble factors that protect AML cells from Ara-C induced cytotoxicity. This leukemia chemoresistance is associated with a decrease in the equilibrative nucleoside transporter (ENT1) activity by inducing removal of ENT1 from the cell surface. Reduction of cell proliferation was also observed with activation of AKT and mTOR-dependent cell survival pathways, which may also contribute to the tumor chemoprotection. Analysis of primary BMSC cultures has demonstrated that AML patients with stroma capable to confer Ara-C resistance in vitro compared to AML patients without this stroma capacity were associated with a worse prognosis. The two year overall survival rate was 0% versus 80% respectively (p=0.0001). This is the first report of a chemoprotection mechanism based on the removal of a drug transporter from the cell surface and most importantly the first time that a stroma phenotype has correlated with prognostic outcome in cancer.