A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia

The hematopoietic stem cell underlying acute myeloid leukemia (AML) is cont roversial. Flow cytometry and the DNA-binding dye Hoechst 33342 were previo usly used to identify a distinct subset of murine hematopoietic stem cells, termed the side population (SP), which rapidly expels Hoechst dye and can reconstitute the bone marrow of lethally irradiated mice. Here, the prevale nce and pathogenic role of SP cells in human AML were investigated. Such ce lls were found in the bone marrow of more than 80% of 61 patients and had a predominant CD34(low/-) immunophenotype. importantly, they carried cytogen etic markers of AML in all 11 cases of active disease examined and in 2 out of 5 cases in complete hematological remission. Comparison of daunorubicin and mitoxantrone fluorescence emission profiles revealed significantly hig her drug eff lux from leukemic SP cells than from non-SP cells. Three of 28 SP cell transplants generated overt AML-like disease in nonobese diabetic- severe combined immunodeficient mice. Low but persistent numbers of leukemi c SP cells were detected by molecular and immunological assays in half of t he remaining mice. Taken together, these findings indicate that SP cells ar e frequently involved in human AML and may be a target for leukemic transfo rmation. They also suggest a mechanism by which SP cells could escape the e ffects of cytostatic drugs and might eventually contribute to leukemia rela pse.