Function of the ABC transporters, P-glycoprotein, multidrug resistance protein and breast cancer resistance protein, in minimal residual disease in acute myeloid leukemia.
OBJECTIVE
Relapse is common in acute myeloid leukemia (AML) because of persistence of minimal residual disease (MRD). ABC-transporters P-glycoprotein (Pgp) and multidrug resistance protein (MRP), are thought to contribute to treatment failure, while it is unknown whether breast cancer resistance protein (BCRP) does so. However, whether up-regulation of pump activity or selection of subpopulations with higher pump activity occurs during chemotherapy is unclear. The aim of this study was to elucidate whether ABC-transporter function changes during the course of disease.


METHODS
MRD cells were identified using leukemia-associated phenotypes combined with a fluorescent probe assay with substrate/modulator: Syto16/ PSC833 (Pgp), calcein-AM/probenecid (MRP) and BODIPY-prazosin/Ko143 (BCRP); efflux profiles were directly compared with blasts at diagnosis and relapse from the same patient.


RESULTS
At diagnosis BCRP activity was undetectable in AML blasts from 23/26 cases, while Pgp activity was present in 36/45 and MRP activity in 26/44 of the cases. Furthermore, no subpopulations of blasts with considerably higher drug efflux capacities were found. Overall, no consistent changes were observed at follow-up [during chemotherapy (n=20), MRD (n=37), relapse (n=26))] in forty-five patients, the mean activities (as percentages of values at diagnosis) were 97% (Pgp), 103% (MRP) and 102% (BCRP).


CONCLUSIONS
Emergence of MRD is thus not accompanied by either upregulation of ABC-transporter function during or after chemotherapy or by selection of pre-existing highly resistant subpopulations. The prognostic value of Pgp and MRP is, therefore, likely related to drug efflux capacity homogeneously distributed in the whole blast population, while BCRP probably has a limited function in drug efflux-related resistance in AML.
van der Pol
Marjolein A
MA
Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Broxterman
Henk J
HJ
Pater
Jennie M
JM
Feller
Nicole
N
van der Maas
Martin
M
Weijers
Geert W D
GW
Scheffer
George L
GL
Allen
John D
JD
Scheper
Rik J
RJ
van Loevezijn
Arnold
A
Ossenkoppele
Gert J
GJ
Schuurhuis
Gerrit J
GJ
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism / Q000502:physiology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000208:Acute Disease; D000328:Adult; D000368:Aged; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000188:drug therapy / Q000473:pathology*; D008137:Longitudinal Studies; D008875:Middle Aged; D009363:Neoplasm Proteins; D018365:Neoplasm, Residual; D011379:Prognosis
C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins