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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

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
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 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
multidrug-resistance gene, cytogenetics, intensity, in-vivo, bcl-2, trial, leukemia, myeloid-leukemia, protein, mdr1 gene, cells, chemotherapy, p-glycoprotein, protein-kinases, age, sample, expression, patient, apoptosis, risk, time, myeloblastic-leukemia, myelodysplastic syndrome, identification, cancer, variant, efflux, polymorphisms
1078-0432
7059-7066
Seedhouse, Claire H.
f27e81ef-25e5-4f23-b2f4-a6bfd93afedc
Grundy, Martin
cf774609-d4b7-4ee8-9d46-d4a79893ae68
White, Paul
21cc3846-ced5-4079-8196-45a2e5476fea
Li, Yun
fbe20681-3f5b-4187-95d8-3e678690e99b
Fisher, Janet
84a276dc-c510-447a-ad93-eb07f7ccae5b
Yakunina, Darya
e2fa3974-2e4c-4c73-a2c1-5a4d120564e4
Moorman, Anthony V.
e4ced178-ee03-47ef-bc5e-25d8453951d5
Hoy, Terence
f34254c0-c2f8-4e85-8fa4-18670c05969f
Russell, Nigel
50041bba-1fd0-47a5-948b-cd8d3e40e426
Burnett, Alan
bcfa23c0-18a0-4e84-8559-4521fa52ff99
Pallis, Monica
995e1c71-2d32-4878-b565-fd613afa3c44
Seedhouse, Claire H.
f27e81ef-25e5-4f23-b2f4-a6bfd93afedc
Grundy, Martin
cf774609-d4b7-4ee8-9d46-d4a79893ae68
White, Paul
21cc3846-ced5-4079-8196-45a2e5476fea
Li, Yun
fbe20681-3f5b-4187-95d8-3e678690e99b
Fisher, Janet
84a276dc-c510-447a-ad93-eb07f7ccae5b
Yakunina, Darya
e2fa3974-2e4c-4c73-a2c1-5a4d120564e4
Moorman, Anthony V.
e4ced178-ee03-47ef-bc5e-25d8453951d5
Hoy, Terence
f34254c0-c2f8-4e85-8fa4-18670c05969f
Russell, Nigel
50041bba-1fd0-47a5-948b-cd8d3e40e426
Burnett, Alan
bcfa23c0-18a0-4e84-8559-4521fa52ff99
Pallis, Monica
995e1c71-2d32-4878-b565-fd613afa3c44

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).

Record type: Article

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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More information

Published date: 1 December 2007
Keywords: multidrug-resistance gene, cytogenetics, intensity, in-vivo, bcl-2, trial, leukemia, myeloid-leukemia, protein, mdr1 gene, cells, chemotherapy, p-glycoprotein, protein-kinases, age, sample, expression, patient, apoptosis, risk, time, myeloblastic-leukemia, myelodysplastic syndrome, identification, cancer, variant, efflux, polymorphisms

Identifiers

Local EPrints ID: 62923
URI: http://eprints.soton.ac.uk/id/eprint/62923
ISSN: 1078-0432
PURE UUID: 78f1efb0-ab03-4fc6-9587-f679f8c8019f

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Date deposited: 04 Sep 2008
Last modified: 15 Mar 2024 11:33

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Contributors

Author: Claire H. Seedhouse
Author: Martin Grundy
Author: Paul White
Author: Yun Li
Author: Janet Fisher
Author: Darya Yakunina
Author: Anthony V. Moorman
Author: Terence Hoy
Author: Nigel Russell
Author: Alan Burnett
Author: Monica Pallis

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