Expression of the mdr 3 gene in prolymphocytic leukemia: Association with cyclosporin‐a‐induced increase in drug accumulation

Typical multidrug resistance in human and animal cell lines is caused by overactivity of an unidirectional transmembrane drug efflux pump, encoded by the MDR genes, called mdr genes in mice and humans and pgp genes in hamsters. In humans, two mdr genes, mdr 1 and mdr 3, with approximately 80% nucleotide homology, have been identified. There is increasing evidence that overexpression of the mdr 1 gene plays a role in resistance to anticancer agents in specific tumor types. However, currently no data are available on a possible role for mdr 3 in drug resistance. Here we report high levels of expression of mdr 3 gene sequences in leukemic cells from 6 out of 6 patients with prolymphocytic leukemia (PLL). No mdr 1 expression was detected in 5 out of 6 of these samples, whereas a low level of mdr 1 expression was found in a sample from one PLL patient in the course of transformation to non‐Hodgkin's lymphoma. Except for this patient, all other PLL cases studied had not received prior chemotherapy. In vitro drug uptake studies showed that daunorubicin accumulation in PLL cells was increased by cyclosporin A. Since cyclosporin A is an inhibitor of the mdr 1‐encoded P‐glycoprotein drug pump, these data suggest that in PLL cells mdr 3 also codes for a drug efflux pump. Our findings could partly explain the primary refractoriness of PLL to chemotherapy.