Adult T-cell leukemia cells over-express the multidrug-resistance-protein (MRP) and lung-resistance-protein (LRP) genes

Adult T-cell leukemia (ATL) is a T-cell malignancy caused by human T-cell-l eukemia-virus-1 (HTLV-I) infection. ATL comprises 4 clinical forms: acute, chronic, smoldering and lymphoma types. ATL is usually resistant to convent ional chemotherapy and has a relatively poor prognosis; however, the resist ance mechanisms remain undetermined. To explore the multidrug-resistance (M DR) mechanisms of ATL, we examined the expression and functional activity o f MDR-related genes in peripheral-blood mononuclear cells (PBMC) from ATL p atients by semi-quantitative RT-PCR and FACScan with calcein-AM. PBMC from ATL patients expressed similar or higher levels of MRP, LRP and cMOAT mRNAs , as compared with normal PBMC. In normal controls and ATL patients, MDR1 m RNA expression was undetectable in this study. PBMC from acute and chronic AIL patients expressed significantly higher levels of MRP and LRP mRNA than did normal PBMC (p < 0.01 and p < 0.05 respectively). In chronic ATL, posi tive correlations were apparent between levels of MRP and LRP mRNA expressi on (r = 0.759, p = 0.018), and between each mRNA level and the absolute num ber of abnormal lymphocytes in peripheral blood. Probenecid, an inhibitor o f the MRP pump, significantly increased the accumulation of calcein in PBMC from 3 chronic ATL patients. Our findings suggest that the MRP and LRP gen es in ATL ave often activated by HTLV-I infection and may confer MDR of ATL cells in vivo. Combined chemotherapy with inhibitors of these MDR genes ma y be promising in the treatment of ATL. (C) 1999 Wiley-Liss, Inc.