MRP3, BCRP, and P-Glycoprotein Activities are Prognostic Factors in Adult Acute Myeloid Leukemia

Abstract

Purpose: P-Glycoprotein (Pgp) is associated with poor outcome in acute myeloid leukemia (AML). We have investigated other ATP-binding cassette proteins such as BCRP, MRP1, MRP2, MRP3, and MRP5 for their potential implication in chemoresistance. Experimental Design and Results: Eighty five AML patient samples were analyzed in this study. First, MRP3 function was higher in patients which had a high level of leukocytes (P = 0.01), a M5 FAB subtype (P = 0.04), and an intermediate or poor cytogenesis (P = 0.05). BCRP activity was not correlated with clinical or biological variables, but high Pgp activity was correlated with the following variables: CD34 expression (P = 0.002), FAB subtype (P = 0.002), intermediate or poor cytogenesis (P = 0.02), and elderly patients (P = 0.03). Second, Pgp, MRP3, and BCRP activities were correlated with complete remission (P = 0.02, P = 0.04, and P = 0.04, respectively), disease-free survival (P = 0.02, P = 0.03, and P = 0.25, respectively), and overall survival (P = 0.04, P = 0.04, and P = 0.05, respectively) in multivariate analysis.The patient samples expressing one or none of these Pgp, MRP3, or BCRP functional proteins have a better prognosis than the patients expressing two or three of these functional proteins (complete remission, P = 0.02; disease-free survival, P = 0.01; overall survival, P < 0.001).Conclusions: BCRP and MRP3 may also be involved in chemoresistance in AML, especially MRP3 in patients with M5 FAB. Additional modulation of BCRP or MRP3 to Pgp modulation may be necessary in some patients in order to improve the treatment outcome.

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

“…The negligible effect of ABCG2 overexpression on CR, different from what has been reported by other groups, 5,7,14 can be explained by the inclusion of fludarabine in the induction we used. In 3 different ABCB1-overexpressing cell-line systems, we previously demonstrated that the use of fludarabine decreases the resistance index more in the resistant sublines than in their parental ones.…”

High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group

“…Using the previously described cutoff criteria, 11,14 67 and 52% of patients presented Pgp expression and activity, respectively, 65 and 62%, respectively, for MRP1 Table 1 Baseline characteristics of patients…”

“…Previous studies have shown that ABC protein activities are prognostic factors in AML. 10,11,15 The role of ABC proteins has been studied in patients treated with GO at a dose of 9 mg/m 2 , and it has been shown that blast cell Pgp expression correlated with treatment failure. 16 It has also been shown that ABCG2 (BCRP) expression and activity were not associated with reduced GO activity in cell lines.…”

“…Pgp, MRP1, MRP2, MRP3, MRP5 and BCRP protein expression was measured by labelling fresh viable cells with UIC2, QCRL3, M2I4, M3II9, M5I1 and BXP-21 monoclonal antibodies, respectively (concentration 5 Â 10 3 mg/ ml), and phycoerythrin-labeled second antibody as described elsewhere. 10,11 Fluorescence was analyzed on a Beckman Coulter (EPICS Altra) flow cytometer. ABC-Protein expression was determined by Kolmorogov-Smirnov (KS) test, which measures the difference between two distribution functions and generates a value ranging from 0 to 1.0.…”

“…We have used JC1 (7.5 mM)7cyclo-sporin A (CsA) (2 Â 10 À6 M) to assess Pgp activity, calcein-AM (10 À6 M)7MK571 (20 Â 10 À6 M) to assess MRP1 activity, mitoxantrone (MITO) (20 Â 10 À6 M)7MK571 to assess MRP3 activity and MITO7fumitremorgin C (10 À5 M) to assess BCRP activity. 11 Intensity of probe fluorescence in the presence or the absence of modulator was compared using the KS test. A higher D-value (ranging from 0 to 1) indicates a wider difference between the two functions, thus a more resistant group of cells.…”