title: Function of the ABC transporters, P-glycoprotein, multidrug resistance protein and breast cancer resistance protein, in minimal residual disease in acute myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjolein A
authors.initials: MA
authors.lastname: van der Pol
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Broxterman
authors.forename: Jennie M
authors.initials: JM
authors.lastname: Pater
authors.forename: Nicole
authors.initials: N
authors.lastname: Feller
authors.forename: Martin
authors.initials: M
authors.lastname: van der Maas
authors.forename: Geert W D
authors.initials: GW
authors.lastname: Weijers
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: John D
authors.initials: JD
authors.lastname: Allen
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Arnold
authors.initials: A
authors.lastname: van Loevezijn
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Gerrit J
authors.initials: GJ
authors.lastname: Schuurhuis
mesh_terms: 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
chemical_list: 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