Breast cancer resistance protein in drug resistance of primitive CD34+38- cells in acute myeloid leukemia.
OBJECTIVE
Acute myeloid leukemia (AML) is considered a stem cell disease. Incomplete chemotherapeutic eradication of leukemic CD34+38- stem cells is likely to result in disease relapse. The purpose of this study was to investigate the role of the breast cancer resistance protein (BCRP/ATP-binding cassette, subfamily G, member 2) in drug resistance of leukemic stem cells and the effect of its modulation on stem cell eradication in AML.


METHODS
BCRP expression (measured flow-cytometrically using the BXP21 monoclonal antibody) and the effect of its modulation (using the novel fumitremorgin C analogue KO143) on intracellular mitoxantrone accumulation and in vitro chemosensitivity were assessed in leukemic CD34+38- cells.


RESULTS
BCRP was preferentially expressed in leukemic CD34+38- cells and blockage of BCRP-mediated drug extrusion by the novel fumitremorgin C analogue KO143 resulted in increased intracellular mitoxantrone accumulation in these cells in the majority of patients. This increase, however, was much lower than in the mitoxantrone-resistant breast cancer cell line MCF7-MR and significant drug extrusion occurred in the presence of BCRP blockage due to the presence of additional drug transport mechanisms, among which ABCB1 and multiple drug resistance protein. In line with these findings, selective blockage of BCRP by KO143 did not enhance in vitro chemosensitivity of leukemic CD34+38- cells.


CONCLUSIONS
These results show that drug extrusion from leukemic stem cells is mediated by the promiscuous action of BCRP and additional transporters. Broad-spectrum inhibition, rather than modulation of single mechanisms, is therefore likely to be required to circumvent drug resistance and eradicate leukemic stem cells in AML.
Raaijmakers
Marc H G P
MH
Department of Hematology and Central Hematology Laboratory, University Medical Center Nijmegen, St. Radboud, 6500 HB Nijmegen, the Netherlands. h.raajmakers@chl.umcn.nl
de Grouw
Elke P L M
EP
Heuver
Leonie H H
LH
van der Reijden
Bert A
BA
Jansen
Joop H
JH
Scheper
Rik J
RJ
Scheffer
George L
GL
de Witte
Theo J M
TJ
Raymakers
Reinier A P
RA
D036541:ADP-ribosyl Cyclase / Q000276:immunology / Q000378:metabolism*; D051997:ADP-ribosyl Cyclase 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000208:Acute Disease; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D018952:Antigens, CD34 / Q000276:immunology / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007951:Leukemia, Myeloid / Q000145:classification / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D008942:Mitoxantrone / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D008942:Mitoxantrone; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1