Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML)

Abstract

Expression of the multidrug resistance proteins P-glycoprotein, encoded by the MDR1 gene, multidrug resistanceassociated protein (MRP1) and the lung resistance-related protein or major vault protein (LRP/MVP) is associated with clinical resistance to chemotherapy in acute myeloid leukemia (AML). Recently, the breast cancer-resistant protein (BCRP), the equivalent of mitoxantrone-resistant protein (MXR) or placental ABC transporter (ABCP), was described in AML. We investigated MDR1, MRP1, LRP/MVP and BCRP mRNA expression simultaneously in 20 paired clinical AML samples from diagnosis and relapse or refractory disease, using quantitative Taqman analysis. In addition, standard assays for P-glycoprotein expression and function were performed. BCRP was the only resistance protein that was expressed at a significantly higher RNA level (median 1.7-fold, P = 0.04) at relapsed/refractory state as compared to diagnosis. In contrast, LRP/MVP mRNA expression decreased as disease evolved (P = 0.02), whereas MDR1 and MRP1 mRNA levels were not different at relapse as compared to diagnosis. Also, at the protein level no difference of MDR1 between diagnosis and relapse was found. A significant co-expression of BCRP and MDR1 was found at diagnosis (r = 0.47, P = 0.04). The present results suggest that BCRP, but not MDR1, MRP1 or LRP/MVP is associated with clinical resistant disease in AML.

The MRP family of drug efflux pumps

“…However, there is currently little direct evidence indicating that the human protein has significant activity toward these two agents. Numerous reports document the expression of MRP1 in cancers that are treated with anthracyclines, camptothecins and etoposide, such as leukemia and breast, colorectal and germ cell, respectively, and in some cases correlations between clinical outcome and expression have been drawn (for examples of recent studies see Ohishi et al, 2002;Sauerbrey et al, 2002;van den Heuvel-Eibrink et al, 2002;Burger et al, 2003;Plasschaert et al, 2003;Zurita et al, 2003). It is reasonable to infer that MRP1 contributes to the inherent sensitivity of cancers in which it is expressed.…”

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

“…The prognostic significance of BCRP and other transporters in leukemias is the subject of some recent review papers (Ross, 2000;van den Heuvel-Eibrink et al, 2000;van der Kolk et al, 2002a).…”

Treatment of childhood acute myeloblastic leukemia: dose intensification improves outcome and maintenance therapy is of no benefit – multicenter studies of the French LAME (Leucémie Aiguë Myéloblastique Enfant) Cooperative Group

“…21 Alternatively, mechanisms other than MDR1 might be responsible for the development of clinical drug resistance. [22][23][24] Cure rate in AML has improved with intensive induction and postremission therapy with optimized timing. The best results were obtained with the most drug-intensive regimens.…”