Multidrug resistance and stem cells in acute myeloid leukemia.

The article by Raaijmakers et al. (1) in this issue reports a provocative study with important implications for therapeutic strategies in acute myelogenous leukemia (AML). Expression of the MDR1 (ABCB1) gene, encoding the multidrug transporter P-glycoprotein (P-gp), is a major negative prognostic factor in adult patients with AMLs (2–4). Attempts to improve clinical outcomes in AML by modulation of P-gp have yielded variable results and limited benefit (3, 5–8). Raaijmakers et al. studied the efflux of mitoxantrone and its inhibition by verapamil and PSC-833 in leukemic and normal bone marrow stem cells (defined as CD34 and CD38 ). Active efflux of mitoxantrone was shown in both leukemic and normal stem cells from all 15 patients, but efflux was not inhibitable in the leukemic stem cells. The investigators hypothesize that the differences between the leukemic and normal stem cells are caused by additional transport mechanisms in the leukemic cells and that modulation of P-gp in leukemic patients may therefore preferentially target normal bone marrow stem cells. These results highlight a number of questions in leukemia therapy.