MDR1/P-GP Expression as A Prognostic Factor in Acute Leukemias

Abstract

P-glycoprotein (P-gp) is often expressed (40–50%) on leukemic cells at diagnosis in acute myelogenous leukemia (AML), and is even more frequently present after treatment failure. Several large cohorts of newly diagnosed AML patients treated with a classical anthracycline + standard doses of cytosine arabinoside were tested for the prognosis value of MDR1 phenotype, and demonstrated an high correlation between a significant increase of MDR1 gene expression and treatment failure (or, better, drug resistance).

This P-gp(+) drug resistance could be due either to a particular phenotype of bad prognosis AML, as it is suggested by the association of myelodysplasia, complex karyo-type and advanced age with MDR1 phenotype, or due primarily to the active efflux of anthracyclines and VP16 in P-gp (+) leukemic cells. Several observations tend to confirm the functional role of the P-gp in clinical drug resistance: (i) using multivariate analysis, MDR1 phenotype appears to be an independent variable, as potent (or higher) as karyo-type and age for predicting in vivo drug resistance; (ii) the prognostic value is limited to the CD34(+)/P-gp(+) phenotype, wich is linked to a functional P-gp; (iii) the in vitro sensitivity to anthracyclines and VP16 is highly correlated with P-gp expression. All these data argue for an early use of P-gp modifier agents in the treatment of AML.

The role of the MDR1 gene in ALL resistance is controversial and marginal compared to the sensitivity of ALL blasts to glucocorticoids, and the frequency of MDR1 phenotype is low at diagnosis, and is increasing only after repetitive chemotherapies.