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Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study

The presence of p53-pathway dysfunction in chronic lymphocytic leukemia (CLL) can be used to identify patients with chemotherapy-refractory disease. Therapeutic responses are known to vary between patients with chemosensitive CLL and may relate to differences in p53-pathway activity. We hypothesized...

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Autores principales: Groves, Michael J, MacCallum, Stephanie F, Boylan, Michael T, Haydock, Sally, Cunningham, Joan, Gelly, Keith, Gowans, Duncan, Kerr, Ron, Coates, Philip J, Tauro, Sudhir
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434363/
https://www.ncbi.nlm.nih.gov/pubmed/22962562
http://dx.doi.org/10.7150/jca.4813
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author Groves, Michael J
MacCallum, Stephanie F
Boylan, Michael T
Haydock, Sally
Cunningham, Joan
Gelly, Keith
Gowans, Duncan
Kerr, Ron
Coates, Philip J
Tauro, Sudhir
author_facet Groves, Michael J
MacCallum, Stephanie F
Boylan, Michael T
Haydock, Sally
Cunningham, Joan
Gelly, Keith
Gowans, Duncan
Kerr, Ron
Coates, Philip J
Tauro, Sudhir
author_sort Groves, Michael J
collection PubMed
description The presence of p53-pathway dysfunction in chronic lymphocytic leukemia (CLL) can be used to identify patients with chemotherapy-refractory disease. Therapeutic responses are known to vary between patients with chemosensitive CLL and may relate to differences in p53-pathway activity. We hypothesized that the magnitude or type of p53-pathway protein expression is heterogeneous in patients with chemosensitive disease and could associate with white cell responses. In this pilot study, changes in p53 and its transcriptional targets, p21/waf1 and MDM2 were analyzed by immunoblotting and densitometry in CLL cells from 10 patients immediately prior to the start of chemotherapy, and after culture for 24 hours (h) with fludarabine (n=7) or chlorambucil (n=3). The in vitro response was also compared to that in vivo in circulating cells pre-treatment, and at 24h and 96h of chemotherapy. Disease responses were evident in all patients after the first treatment-cycle. Significant p53 induction was observed in CLL cells treated in vitro and in vivo. Greater heterogeneity in the expression-intensity was observed in vivo (σ2=45.15) than in vitro (σ2=1.33) and the results failed to correlate (r(2)=0.18, p=0.22). p21/waf1 and MDM2 expression-profiles were also dissimilar in vitro and in vivo. Higher in vivo (but not in vitro) responses associated with changes in white cell count (p=0.026). Thus, heterogeneity of p53-pathway activity exists in chemosensitive CLL; in unselected patients, in vivo changes do not correlate with those in vitro, but may associate with post-treatment white cell responses.
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spelling pubmed-34343632012-09-07 Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study Groves, Michael J MacCallum, Stephanie F Boylan, Michael T Haydock, Sally Cunningham, Joan Gelly, Keith Gowans, Duncan Kerr, Ron Coates, Philip J Tauro, Sudhir J Cancer Research Paper The presence of p53-pathway dysfunction in chronic lymphocytic leukemia (CLL) can be used to identify patients with chemotherapy-refractory disease. Therapeutic responses are known to vary between patients with chemosensitive CLL and may relate to differences in p53-pathway activity. We hypothesized that the magnitude or type of p53-pathway protein expression is heterogeneous in patients with chemosensitive disease and could associate with white cell responses. In this pilot study, changes in p53 and its transcriptional targets, p21/waf1 and MDM2 were analyzed by immunoblotting and densitometry in CLL cells from 10 patients immediately prior to the start of chemotherapy, and after culture for 24 hours (h) with fludarabine (n=7) or chlorambucil (n=3). The in vitro response was also compared to that in vivo in circulating cells pre-treatment, and at 24h and 96h of chemotherapy. Disease responses were evident in all patients after the first treatment-cycle. Significant p53 induction was observed in CLL cells treated in vitro and in vivo. Greater heterogeneity in the expression-intensity was observed in vivo (σ2=45.15) than in vitro (σ2=1.33) and the results failed to correlate (r(2)=0.18, p=0.22). p21/waf1 and MDM2 expression-profiles were also dissimilar in vitro and in vivo. Higher in vivo (but not in vitro) responses associated with changes in white cell count (p=0.026). Thus, heterogeneity of p53-pathway activity exists in chemosensitive CLL; in unselected patients, in vivo changes do not correlate with those in vitro, but may associate with post-treatment white cell responses. Ivyspring International Publisher 2012-08-24 /pmc/articles/PMC3434363/ /pubmed/22962562 http://dx.doi.org/10.7150/jca.4813 Text en © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
spellingShingle Research Paper
Groves, Michael J
MacCallum, Stephanie F
Boylan, Michael T
Haydock, Sally
Cunningham, Joan
Gelly, Keith
Gowans, Duncan
Kerr, Ron
Coates, Philip J
Tauro, Sudhir
Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study
title Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study
title_full Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study
title_fullStr Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study
title_full_unstemmed Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study
title_short Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study
title_sort heterogeneity of p53-pathway protein expression in chemosensitive chronic lymphocytic leukemia: a pilot study
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434363/
https://www.ncbi.nlm.nih.gov/pubmed/22962562
http://dx.doi.org/10.7150/jca.4813
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