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Correlation of multidrug resistance (MDR1) protein expression with
functional dye/drug efflux in acute myeloid leukemia by multiparameter flow
cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux-
cases
CP Leith, IM Chen, KJ Kopecky, FR Appelbaum, DR Head, JE Godwin, JK Weick and CL Willman
University of New Mexico School of Medicine, Department of Pathology,
Albuquerque, NM, USA.
Resistance to chemotherapy is a major factor limiting successful treatment
of acute myeloid leukemia (AML); one of the best characterized drug
resistance mechanisms is extrusion of drugs by the energy-dependent
multidrug resistance (MDR1) transport protein. Expression of MDR1 is common
in AML and has been linked to lower remission induction rates and decreased
remission durations. Because MDR1 efflux function may be modified by drugs
such as cyclosporin A, accurate identification of MDR1+/efflux+ AML cases
will be critical to identify patients who may benefit from therapies that
contain such MDR1 modulators. We have optimized single and multiparameter
flow cytometric assays to detect efflux of drugs or fluorescent dyes by
previously cryopreserved AML blasts. These assays allowed precise
identification of efflux by leukemic blasts, and correlation with CD34 and
MDR1 expression. We subsequently studied a series of 60 previously
untreated AML cases. Functional efflux was identified in 39 cases and was
significantly correlated with MDR1 expression (P = .0002). However,
discrepant cases were identified; 10 cases were efflux+ without significant
MDR1 expression, whereas 6 MDR1+ cases were efflux-. There was also a
highly significant correlation of efflux with CD34; 31 (79%) of the 39
efflux+ cases were CD34+ in comparison with only 5 (24%) of the 21 efflux-
cases (P < .0001). Multivariate analysis showed that efflux was
significantly associated with independent effects of both CD34 (P = .0011)
and MDR1 expression (P = .034); the majority of efflux+ cases were CD34+,
whereas 5 of the 6 MDR1+ efflux- cases lacked CD34 expression. Cyclosporin
A blocked efflux in all but 2 cases regardless of MDR1 expression.
Functional efflux in AML is frequently detected without the classic MDR1+
phenotype indicating that alternate non-MDR1-mediated efflux mechanisms may
be important. Efflux assays may better identify patients who would benefit
from therapies that include efflux modulators.
Volume 86,
Issue 6,
pp. 2329-2342,
09/15/1995
Copyright © 1995 by The American Society of Hematology
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