Expression of the multidrug resistance gene product (P-glycoprotein) in myelodysplasia is associated with a stem cell phenotype.
Previous studies have indicated relative resistance to chemotherapy in the myelodysplastic syndromes (MDS) and associated acute leukaemia. To determine if multidrug resistance may contribute to chemoresistance in these disorders, we studied bone marrow specimens for P-glycoprotein expression (P-GP) by immunocytochemical staining with monoclonal antibodies reactive with cytoplasmic (C219) or surface epitopes (MRK16) of P-GP. Forty-five case specimens from 43 patients were studied, including 32 cases of primary MDS, seven cases of acute myeloid leukaemia (AML) following MDS, and six therapy-related haematological disorders. Cytogenetic analysis was available on 36 specimens. Two staining patterns were detected: (1) cytoplasm and plasma membrane, and (2) staining restricted primarily to the nuclear-cytoplasmic junction. P-GP was detected in seven (22%) cases of primary MDS, four (57%) cases of AML evolving from MDS, and five (83%) cases of therapy-related haematological disorders. Expression of P-GP was restricted to blasts and leukaemic monocytes, and was otherwise absent from terminally differentiated blood cells. Analysis of the relation between P-GP expression and reactivity with the human progenitor cell antigen CD34, revealed a highly significant association (P = 0.001). P-GP reactivity was distributed equally among normal and abnormal karyotypes and did not correlate with specific cytogenetic abnormalities. These findings indicate that multidrug resistance in MDS and karyotypically-related haematological disorders is closely linked to a stem cell phenotype and may contribute to chemoresistance in these disorders.
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University of Arizona Health Sciences Center, Tucson.
Spier
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Cline
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Doll
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Garewal
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Morgan
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Sandberg
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D001853:Bone Marrow / Q000276:immunology; D004317:Doxorubicin / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D013234:Stem Cells / Q000276:immunology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D008562:Membrane Glycoproteins; D004317:Doxorubicin