Seedhouse, Claire H., Grundy, Martin, White, Paul, Li, Yun, Fisher, Janet, Yakunina, Darya, Moorman, Anthony V., Hoy, Terence, Russell, Nigel, Burnett, Alan and Pallis, Monica (2007) 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, 13 (23), 7059-7066. (doi:10.1158/1078-0432.CCR-07-1484).
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 geneABCB1. Results: Age, lowWBC count, high bcl-2, secondaryAML and myelodysplastic syndrome, and adverse cytogenetics all correlated strongly with high Pgp (MRK16) protein expression. However, ABC131 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 Amean fluorescence intensity of 75th centile sample = 9 units forTT 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 -40% of cases in which m RNA and protein are detectable. Moreover, leukemia-specific factors, such as lowWBC count and poor risk cytogenetics, have a much greater effect than genetic polymorphisms on Pgp expression in AML blasts
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