Reduced function of the multidrug resistance P-glycoprotein in CD34+ cells of patients with aplastic anaemia

Drug exposure is implicated in the aetiology of some cases of acquired aplastic anaemia (AA), but the reason for this susceptibility remains unclear. We previously demonstrated that P-glycoprotein (P-gp) function, a drug efflux pump, is decreased in AA lymphocytes. To further evaluate whether P-gp activity is also abnormal in AA stem cells, we examined bone marrow (BM) CD34+ cells from newly diagnosed AA patients (AA-d, n = 25), after immunosuppression (AA-IST, n = 13) and after BM transplantation (AA-BMT, n = 8). Of the AA patients with autologous haematopoiesis (AA-d + AA-IST), 15 had drug-induced AA. Thirty-two BM donors were studied as controls. P-glycoprotein function was assessed by the rhodamine 123-efflux assay. P-glycoprotein function in CD34+ cells was reduced in AA-d patients (17.8%, 0-67.7) compared with controls (42.5%, 13.4-57.4; P < 0.001), as well as in AA-IST (20.3%, 1.2-32.0; P < 0.001), but not in AA-BMT (40.9%, 19.0-55.9). P-gp function was reduced more in drug-induced AA (14.5%, 0-27.4) than in the other cases (26.1%, 0-67.7; P = 0.04), but it did not correlate with disease severity. These results indicate that P-gp function is defective in AA CD34+ cells, pointing to a role of P-gp in increased cell susceptibility to xenobiotics in AA.