BACKGROUND AND OBJECTIVES: 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. DESIGN AND 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). INTERPRETATION AND 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.
BACKGROUND AND OBJECTIVES: 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. DESIGN AND 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). INTERPRETATION AND 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: Carla S Wilson; George S Davidson; Shawn B Martin; Erik Andries; Jeffrey Potter; Richard Harvey; Kerem Ar; Yuexian Xu; Kenneth J Kopecky; Donna P Ankerst; Holly Gundacker; Marilyn L Slovak; Monica Mosquera-Caro; I-Ming Chen; Derek L Stirewalt; Maurice Murphy; Frederick A Schultz; Huining Kang; Xuefei Wang; Jerald P Radich; Frederick R Appelbaum; Susan R Atlas; John Godwin; Cheryl L Willman Journal: Blood Date: 2006-04-04 Impact factor: 22.113
Authors: Brian Van Ness; Christine Ramos; Majda Haznadar; Antje Hoering; Jeff Haessler; John Crowley; Susanna Jacobus; Martin Oken; Vincent Rajkumar; Philip Greipp; Bart Barlogie; Brian Durie; Michael Katz; Gowtham Atluri; Gang Fang; Rohit Gupta; Michael Steinbach; Vipin Kumar; Richard Mushlin; David Johnson; Gareth Morgan Journal: BMC Med Date: 2008-09-08 Impact factor: 8.775
Authors: Marry M van den Heuvel-Eibrink; Bronno van der Holt; Alan K Burnett; Wolfgang U Knauf; Martin F Fey; Gregor E G Verhoef; Edo Vellenga; Gert J Ossenkoppele; Bob Löwenberg; Pieter Sonneveld Journal: Ann Hematol Date: 2007-03-06 Impact factor: 3.673