Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia

• Published in: Clinical cancer research Vol. 11; no. 6; pp. 2436 - 2444
• Main Authors: RAAIJMAKERS, Marc H. G. P, DE GROUW, Elke P. L. M, HEUVER, Leonie H. H, VAN DER REIJDEN, Bert A, JANSEN, Joop H, SCHEPER, Rik J, SCHEFFER, George L, DE WITTE, Theo J. M, RAYMAKERS, Reinier A. P
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2005
• Subjects: Acute Disease; ADP-ribosyl Cyclase - immunology; ADP-ribosyl Cyclase - metabolism; ADP-ribosyl Cyclase 1; Adult; Aged; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, CD34 - immunology; Antigens, CD34 - metabolism; Antineoplastic agents; Antineoplastic Agents - metabolism; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Bone Marrow - immunology; Bone Marrow - metabolism; Drug Resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid - classification; Leukemia, Myeloid - immunology; Leukemia, Myeloid - metabolism; Leukemias and lymphomas; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Membrane Glycoproteins; Middle Aged; Mitoxantrone - metabolism; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Stem Cell Biology; Stem Cells - cytology; Stem Cells - immunology; Stem Cells - metabolism; Tumor Cells, Cultured; Primitive; Treatment resistance; Acute; Malignant hemopathy; In vitro; Breast cancer resistance protein; Acute myelocytic leukemia
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-0212

Purpose: 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. Experimental Design: 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.