Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1.
Tetramethylrosamine (TMR) is excluded from P-glycoprotein (MDR1)-enriched cell lines, but it stains efficiently MDR1-poor parent lines. Application of the TMR resistance assay to cells obtained from chronic myelogenous leukaemia (CML) patients revealed, in all individuals, a significant resistance compared with healthy donors (P < 0.001). Cells from the same patients at later phases exhibited a further increase in TMR resistance. Doxorubicin was excluded from all cell samples obtained from CML patients at presentation. The resistance to TMR and doxorubicin was energy-dependent, and was not modulated by inhibitors of MDR1 and multidrug-resistance protein-1 (MRP1). Transcription of mRNAs suspected as relevant to multidrug resistance was assessed using comparative reverse transcription polymerase chain reaction. All cells from the CML patients transcribed high levels of MRP3, MRP4 and MRP5 compared with healthy donors. Low levels of MDR1, MRP1, MRP2, MRP6, lung resistance-related protein and anthracycline resistance-associated protein were equally transcribed in cells from healthy donors and CML patients. These results indicated that neither MDR1 nor MRP1 mediate the resistance in these cells. Our results shed light on a resistance mechanism operative in CML patients, which, together with the resistance to apoptosis, is responsible for the lack of response of CML patients to induction-type protocols used to treat acute myeloid leukaemia patients.
Carter
A
A
Haematology Department and Blood Bank, Rambam Medical Centre, Haifa, Israel.
Dann
E J
EJ
Katz
T
T
Shechter
Y
Y
Oliven
A
A
Regev
R
R
Eytan
E
E
Rowe
J M
JM
Eytan
G D
GD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D016022:Case-Control Studies; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004317:Doxorubicin; D018432:Drug Resistance, Multiple; D005656:Fungal Proteins / Q000235:genetics; D019450:Genes, MDR; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123; D012235:Rhodamines; D012269:Ribosomal Proteins / Q000235:genetics; D014158:Transcription, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D004317:Doxorubicin; D005656:Fungal Proteins; D006575:Heterocyclic Compounds, 3-Ring; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011768:Pyruvate Dehydrogenase Complex; D012333:RNA, Messenger; D020112:Rhodamine 123; D012235:Rhodamines; D012269:Ribosomal Proteins; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human; C412715:tetramethylrosamine; C067358:MRP-3 protein, Neurospora crassa