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.
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.
Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Patricia
P
Macanas-Pirard
Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.|Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
Richard
R
Broekhuizen
Facultad de Medicina, Universidad San Sebastián, Center for Aging and Regeneration (CARE), Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Alfonso
A
González
Facultad de Ciencia, Universidad San Sebastián, Fundación Ciencia y Vida, Santiago, Chile.
Claudia
C
Oyanadel
Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Daniel
D
Ernst
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.|Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
Patricia
P
García
Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Viviana P
VP
Montecinos
Department of Physiology, Millennium Nucleus for Regenerative Biology, Faculty of Biology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Felipe
F
Court
Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Mauricio
M
Ocqueteau
Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Región de los Ríos, Chile.
Pablo
P
Ramirez
Department of Hematology and Oncology, UC-Center for Investigation in Translational Oncology (CITO), Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.|Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.
Bruno
B
Nervi
D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000473:pathology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D063868:Patient Outcome Assessment; D017154:Stromal Cells / Q000473:pathology
D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D003561:Cytarabine
ENT1; biomarker; bone marrow stroma; cytarabine-resistance; leukemia