Low levels of ABCG2 expression in adult AML blast samples.
Previous reports have suggested that the adenosine triphosphate-binding cassette protein ABCG2 (breast cancer resistance protein [BCRP], mitoxantrone resistance [MXR]) is associated with drug resistance in acute myeloid leukemia (AML). The aims of this study were to determine the level of ABCG2 mRNA expression necessary to produce drug resistance and to define the ABCG2 levels in normal bone marrow (BM), peripheral blood (PB), cord blood (CB), and adult AML blast cell populations. First, using transduced clonal cell lines expressing varying levels of ABCG2, we found that ABCG2 expression conferred resistance to mitoxantrone and topotecan, but not to idarubicin. Next, we developed a real-time reverse transcription-polymerase chain reaction assay for measuring ABCG2 mRNA expression levels in clinical samples. Normal BM and PB contained low levels of ABCG2 mRNA, while higher levels were measured in CB mononuclear cells, CD34(+), and Ac133(+) populations, consistent with the known stem cell enrichment in these populations. Next, we studied the ABCG2 mRNA levels in 40 specimens from newly diagnosed adult AML patients. Only 7% of these samples contained ABCG2 mRNA levels within the range of our drug-resistant clone, although another 78% were higher than normal blood and bone marrow. Flow cytometry revealed very small subpopulations of ABCG2-expressing cells in the cases we examined. Our data suggest that high levels of ABCG2 mRNA expression in adult AML blast specimens are relatively uncommon and that ABCG2 expression may be limited to a small cell subpopulation in some cases.
Abbott
Brian L
BL
Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Colapietro
Anne-Marie
AM
Barnes
Yuxiao
Y
Marini
Frank
F
Andreeff
Michael
M
Sorrentino
Brian P
BP
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001773:Blood Cells / Q000737:chemistry; D001854:Bone Marrow Cells / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology; D007231:Infant, Newborn; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000737:chemistry* / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D019772:Topotecan / Q000494:pharmacology
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019772:Topotecan; D008942:Mitoxantrone; D015255:Idarubicin