Enhanced MDR1 Gene Expression in Human T-Cell Leukemia
Virus-I-Infected Patients Offers New Prospects for Therapy
Alan Lau,
Simon Nightingale,
Graham P. Taylor,
Timothy W. Gant, and
Alan J. Cann
From the Department of Microbiology and Immunology, and MRC
Toxicology Unit, University of Leicester, Leicester; the Queen
Elizabeth Neuroscience Centre, Queen Elizabeth Hospital, Birmingham;
and St Mary's Hospital Medical School, London, UK.
Overexpression of P-glycoprotein (P-gp), the protein product of the
multidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. This phenotype is reminiscent of human T-cell leukemia virus (HTLV)-transformed leukemic cells, for which no consistently effective chemotherapeutic regime has been found. The
presence of an active multiple drug resistance (MDR) phenotype in
freshly isolated peripheral blood mononuclear cells (PBMC) from
HTLV-I-infected subjects was investigated. Significant P-gp-mediated efflux activity and enhanced MDR1 mRNA expression was observed in nine of 10 HTLV-infected subjects. The development of MDR phenotypes was found to be independent of disease type or status with significant MDR activities being observed in adult T-cell leukemia (ATL), HTLV-associated myelopathy (HAM)/tropical spastic paraparesis (TSP),
and asymptomatic HTLV-infected individuals. P-gp-mediated drug efflux
was also found to be restricted to CD3+ T-cell
populations. Furthermore, we show the novel finding that the
MDR1 gene promoter is transcriptionally activated by the HTLV-I tax protein, suggesting a molecular basis for the development of drug
resistance in HTLV-I infections. These observations open up the
possibility of new chemotherapeutic approaches to HTLV-associated diseases through the use of P-gp inhibitors.
Blood, Vol. 91 No. 7 (April 1), 1998:
pp. 2467-2474
© 1998 by The American Society of Hematology.
