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.

Patricia Macanas-Pirard,Bruno Nervi,Alfonso González,Daniel Ernst,Claudia Oyanadel,Viviana P Montecinos,Felipe Court,Pablo Ramirez,Patricia García,Mauricio Ocqueteau,Richard Broekhuizen

doi:10.18632/oncotarget.14981

Patricia Macanas-Pirard, Bruno Nervi + Show 9 more

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https://doi.org/10.18632/oncotarget.14981

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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.

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Acute myeloid leukemia (AML) is a group of neoplastic disorders characterized by the clonal accumulation of immature myeloblasts in the bone marrow (BM) and peripheral blood (PB)
We previously reported that mobilization of leukemia cells away from the BM niche into the PB induced by CXCR4 inhibitor AMD3100, increased significantly the overall survival of mice treated with Ara-C [7]
We have previously shown that murine bone marrow stroma cells (BMSCs) supernatant (SN) contains soluble factors that protect murine leukemia cells from Ara-C induced cytotoxicity in vitro

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Introduction

Acute myeloid leukemia (AML) is a group of neoplastic disorders characterized by the clonal accumulation of immature myeloblasts in the bone marrow (BM) and peripheral blood (PB). The treatment of AML has improved substantially over the past few decades, the prognosis continues to be relatively poor. The most effective agent for the treatment of AML is cytarabine (Ara-C), which is the cornerstone of all standard chemotherapy regiments [2]. Ara-C is a nucleoside analogue which functions by inhibiting DNA synthesis. It is incorporated into cancer www.impactjournals.com/oncotarget cells using specialized membrane transport proteins [3], the human equilibrative nucleoside transporter-1 (ENT1) responsible for 80% of Ara-C uptake in human leukemia cells [4]

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