Abstract
BackgroundDespite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells.MethodsUsing a leukemia mouse model and a human leukemia cell line, we studied the interaction of leukemia cells with the BM microenvironment. We evaluated in vivo and in vitro leukemia cell chemoprotection to different cytotoxic agents mediated by the BM stroma. Leukemia cell apoptosis was assessed by flow cytometry and western blotting. The activity of the equilibrative nucleoside transporter 1 (ENT1), responsible for cytarabine cell incorporation, was investigated by measuring transport and intracellular accumulation of 3H-adenosine.ResultsLeukemia cell mobilization from the bone marrow into peripheral blood in vivo using a CXCR4 inhibitor induced chemo-sensitization of leukemia cells to cytarabine, which translated into a prolonged survival advantage in our mouse leukemia model. In vitro, the BM stromal cells secreted a soluble factor that mediated significant chemoprotection to leukemia cells from cytarabine induced apoptosis. Furthermore, the BM stromal cell supernatant induced a 50% reduction of the ENT1 activity in leukemia cells, reducing the incorporation of cytarabine. No protection was observed when radiation or other cytotoxic agents such as etoposide, cisplatin and 5-fluorouracil were used.ConclusionThe BM stroma secretes a soluble factor that significantly protects leukemia cells from cytarabine-induced apoptosis and blocks ENT1 activity. Strategies that modify the chemo-protective effects mediated by the BM microenvironment may enhance the benefit of conventional chemotherapy for patients with AML.
Highlights
Acute myeloid leukemia (AML) is a clonal disorder of the hematopoietic stem cell (HSC) characterized by the accumulation of myeloblasts in the bone marrow (BM) and peripheral blood
We have previously described a murine leukemia model that exhibits the characteristics of microenvironment-mediated drug resistance, and we showed that the interaction between leukemia cells and the stroma can be blocked in vivo by AMD3100, a small molecule inhibitor of CXCR4 that mobilizes normal hematopoietic stem cells and leukemic blasts from hematopoietic niches into the peripheral blood
To further understand the mechanisms involved in this chemoprotection conferred by the BM stroma, we developed in this study an in vitro co-culture system of a mouse BM derived stromal cell line and leukemia cells to determine the effect of stromal cells on leukemia cell apoptosis induced by cytotoxic agents
Summary
Acute myeloid leukemia (AML) is a clonal disorder of the hematopoietic stem cell (HSC) characterized by the accumulation of myeloblasts in the bone marrow (BM) and peripheral blood. Despite a high response rate to chemotherapy, the vast majority of patients with AML relapse due to residual disease in the BM. [4,5,6] the interaction of leukemia cells with the BM stroma has been proposed as a mechanism for chemotherapy resistance. The ENTs are integral membrane proteins responsible for the uptake of a large number of nucleosides broadly used in cancer treatment such as Ara-C, gemcitabine, and fludarabine. Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). We propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells
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