Expression of Multidrug Resistance–Associated Proteins Predicts Prognosis in Childhood and Adult Acute Lymphoblastic Leukemia

Abstract

Purpose: Patients with acute lymphoblastic leukemia (ALL) are treated with a variety of chemotherapeutic drugs, which can be transported by six multidrug resistance^associated proteins (MRP). These MRPs have strongly overlapping functional activities. The aim of this study was to investigate the expression levels of MRP1to MRP6 and study their effect on prognosis. Experimental Design: The mRNA expression levels of MRP1 to MRP6 were analyzed by quantitative real-time PCR in leukemic blasts of105 de novo ALL patients (adults, n = 49; children, n = 56) including 70% B-lineage and 30% T-lineage ALL patients. Results: Adults showed a higher expressions of MRP1 (P = 0.008), MRP2 (P = 0.026), and MRP3 (P = 0.039) than children. Interestingly, this difference disappeared when patients were categorized based on clinical outcome. Relapsed patients showed a higher expression of all MRP genes, except MRP4. For the total group of ALL patients, the expressions of MRP1, MRP2, MRP3, MRP5, and MRP6 predicted relapse. Moreover, high expression of all MRP genes, except MRP4, was associated with a reduced relapse-free survival in children and adults (MRP1, P = 0.005; MRP2, P = 0.008; MRP3, P = 0.001; MRP5, P = 0.016; MRP6, P = 0.037).Conclusions: The present study shows that a subset of ALL patients with high MRP expression has an unfavorable prognosis independently of age.

Induction of Multiple Drug Transporters by Efavirenz

“…For P-gp /ABCB1, we confirmed that also activity was increased while other transporter activities have not been assessed. It is not imperative, that mRNA levels translate into protein or activity levels, although in the majority of cases, variations in transporter mRNA levels were associated with changes in the corresponding protein (40) or with altered function (7,35,36,40,41). Hence while a similar correlation for other transporters may be assumed, it has not been established by this study.…”

ABCA3 as a Possible Cause of Drug Resistance in Childhood Acute Myeloid Leukemia

“…Benderra et al found the same results in adult patients with AML (14,15). MRP3 is also associated with drug resistance in childhood ALL (16,17).…”

“…The only important difference was a higher number of patients with the chromosomal aberration inv (16) in the GR group (Table 1). However, the expression of ABCA3 was not associated with this inversion.…”

“…The four genes were investigated for their association with sex, age, FAB type, initial WBC, initial percentage of leukemic cells in WBC, and the presence of Auer rods and chromosomal aberrations t(8;21), t(9;11), and inv (16). The only associations that were statistically significant were a trend for higher levels of ABCA2 in patients with a higher percentage of leukemic cells in the initial WBC count (P = 0.005; Spearman's correlation coefficient = 0.47) a trend for lower levels of ABCA3 in older patients (P = 0.041; Spearman's correlation coefficient = À0.29), and a trend for higher levels of ABCC10 in patients with a higher initial WBC count (P = 0.034; Spearman's correlation coefficient = 0.31).…”

Up-regulation of P-glycoprotein confers acquired resistance to 6-mercaptopurine in human chronic myeloid leukemia cells

“…The overexpression of P-gp and MRP1 was shown to correlate with short survival in patients with adult T-cell leukemia (9,10). However, over the last two decades, it has become evident that P-gp is not the only human ABC transporter that, at least in vitro, is able to confer resistance to clinically significant chemotherapeutic agents leading to MDR (1,3,(11)(12)(13)(14)(15)(16).…”