ENHANCED MDR1 GENE-EXPRESSION IN HUMAN T-CELL LEUKEMIA VIRUS-I-INFECTED PATIENTS OFFERS NEW PROSPECTS FOR THERAPY

Overexpression of P-glycoprotein (P-gp), the protein product of the mu ltidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. This phenotype is reminiscent of human T-cell leukemia virus (H TLV)-transformed leukemic cells. for which no consistently effective c hemotherapeutic regime has been found. The presence of an active multi ple drug resistance (MDR) phenotype in freshly isolated peripheral blo od mononuclear cells (PBMC) from HTLV-l-infected subjects was investig ated. Significant P-gp-mediated efflux activity and enhanced MDR1 mRNA expression was observed in nine of 10 HTLV-infected subjects. The dev elopment of MDR phenotypes was found to be independent of disease type or status with significant MDR activities being observed in adult T-c ell leukemia (ATL), HTLV-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). and asymptomatic HTLV-infected individuals. P-gp-me diated drug efflux was also found to be restricted to CD3(+) T-cell po pulations. Furthermore, we show the novel finding that the MDR1 gene p romoter is transcriptionally activated by the HTLV-I tax protein, sugg esting a molecular basis for the development of drug resistance in HTL V-I infections. These observations open up the possibility of new chem otherapeutic approaches to HTLV-associated diseases through the use of P-gp inhibitors. (C) 1998 by The American Society of Hematology.