Article: Sequential influences of leukemia-specific and genetic factors on p-glycoprotein expression in blasts from 817 patients entered into the National Cancer Research Network acute myeloid leukemia 14 and 15 trials.
Clinical cancer research : an official journal of the American Association for Cancer Research
2007 Volume 13, Issue 23, Page(s) 7059–7066
Abstract: Purpose: P-glycoprotein (Pgp) is a major prognostic factor for chemotherapy failure in acute myeloid leukemia (AML). This study compared the influence of genetic and leukemia-specific factors on Pgp.: Experimental design: Eight hundred and seventeen ... ...
| Abstract | Purpose: P-glycoprotein (Pgp) is a major prognostic factor for chemotherapy failure in acute myeloid leukemia (AML). This study compared the influence of genetic and leukemia-specific factors on Pgp. Experimental design: Eight hundred and seventeen samples were studied prospectively for Pgp protein expression and function and G1199A, G2677T, and C3435T polymorphisms in the encoding gene ABCB1. Results: Age, low WBC count, high bcl-2, secondary AML and myelodysplastic syndrome, and adverse cytogenetics all correlated strongly with high Pgp (MRK16) protein expression. However, ABCB1 3435TT homozygosity was negatively correlated with Pgp. Pgp protein is only expressed in 41% of samples such that the negative effect of the polymorphism was not seen at baseline Pgp levels but was marked in the upper 41% of samples (MRK16 Deltamean fluorescence intensity of 75th centile sample = 9 units for TT variant samples and 26 units for CC/CT; P = 0.003). However, no association was found between genetic factors and Pgp function using rhodamine 123 accumulation. Conclusions: The genetic polymorphism 3435TT (which results in unstable mRNA) has a significant effect on Pgp expression, but this is only seen in approximately 40% of cases in which mRNA and protein are detectable. Moreover, leukemia-specific factors, such as low WBC count and poor risk cytogenetics, have a much greater effect than genetic polymorphisms on Pgp expression in AML blasts. |
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| MeSH term(s) | ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1/biosynthesis ; ATP-Binding Cassette, Sub-Family B, Member 1/genetics ; Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Bone Marrow Cells/metabolism ; Child ; Clinical Trials as Topic ; Haplotypes ; Humans ; Leukemia, Myeloid, Acute/blood ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Leukocytes, Mononuclear/metabolism ; Middle Aged ; Phenotype ; Polymorphism, Genetic ; Polymorphism, Restriction Fragment Length ; Prospective Studies ; Proto-Oncogene Proteins c-bcl-2/blood | |||||
| Chemical Substances | ABCB1 protein, human ; ATP Binding Cassette Transporter, Sub-Family B ; ATP-Binding Cassette, Sub-Family B, Member 1 ; Proto-Oncogene Proteins c-bcl-2 | |||||
| Language | English | |||||
| Publishing date | 2007-12-01 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1225457-5 | |||||
| ISSN | 1557-3265 ; 1078-0432 | |||||
| ISSN (online) | 1557-3265 | |||||
| ISSN | 1078-0432 | |||||
| DOI | 10.1158/1078-0432.CCR-07-1484 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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