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

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 Δmean 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 f40% 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.