MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia

The expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, is an in dependent adverse prognostic factor for response and survival in de novo ac ute myeloid leukemia (AML), Little is known about MDR1 expression during th e development of disease. The present study investigated whether MDR1 gene- related clonal selection occurs in the development from diagnosis to relaps ed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Exp ression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients wi th AML, Thirteen patients were homozygous for the genetic polymorphism of M DR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were hete rozygous (GT), In the heterozygous patients, no selective loss of one allel e was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was as sociated with shorter relapse-free intervals (P = .002) and poor survival r ates (P = .02), compared with heterozygous patients. No difference was foun d in P-gp expression or function in patients with AML with either of the al lelic variants of the MDR1 gene. It was concluded that P-gp function or exp ression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene-related clonal selection does not occur when AML evolves to recurrent disease.