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Low levels of ABCG2 expression in adult AML blast samples
Brian L Abbott1, Anne-Marie Colapietro, Yuxiao Barnes
1Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Abstract:
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.
Insights
High ABCG2 (adenosine triphosphate-binding cassette protein) mRNA expression is uncommon in adult acute myeloid leukemia (AML) blast cells, suggesting limited drug resistance conferred by this protein in most AML patients.
Area of Science:
- Molecular Biology
- Hematology
- Oncology
Background:
- The adenosine triphosphate-binding cassette protein ABCG2, also known as breast cancer resistance protein (BCRP), is implicated in drug resistance in acute myeloid leukemia (AML).
- Understanding ABCG2 expression levels is crucial for predicting drug response in AML patients.
Purpose of the Study:
- To determine the ABCG2 mRNA expression level required for drug resistance in AML.
- To quantify ABCG2 mRNA levels in normal bone marrow, peripheral blood, cord blood, and adult AML blast cells.
Main Methods:
- Utilized transduced cell lines with varying ABCG2 expression to assess drug resistance.
- Developed a real-time reverse transcription-polymerase chain reaction assay for clinical sample analysis.
- Employed flow cytometry to identify ABCG2-expressing cell subpopulations.
Main Results:
- ABCG2 expression conferred resistance to mitoxantrone and topotecan, but not idarubicin.
- Normal bone marrow and peripheral blood showed low ABCG2 mRNA levels.
- Cord blood and stem cell populations exhibited higher ABCG2 mRNA levels.
- Only 7% of newly diagnosed adult AML samples had ABCG2 mRNA levels associated with drug resistance, though 78% were higher than normal controls.
- Flow cytometry detected very small subpopulations of ABCG2-expressing cells in AML samples.
Conclusions:
- High ABCG2 mRNA expression is infrequent in adult AML blast specimens.
- ABCG2-mediated drug resistance may be confined to small cell subpopulations in some AML cases.
- These findings suggest a limited role for widespread ABCG2 expression in driving drug resistance in the majority of adult AML patients.