J Cancer 2012; 3:354-361. doi:10.7150/jca.4813

Research Paper

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

Michael J Groves1*, Stephanie F MacCallum1*, Michael T Boylan1, Sally Haydock2, Joan Cunningham2, Keith Gelly3, Duncan Gowans3, Ron Kerr3, Philip J Coates1,4, Sudhir Tauro1,3✉

1. Dundee Cancer Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom. DD19SY;
2. Department of Cytogenetics, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom. DD19SY;
3. Department of Haematology, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom. DD19SY;
4. Tayside Tissue Bank, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom. DD19SY.
* MJG and SFM contributed equally as first authors.

Abstract

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 (r2=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.

Keywords: p53, CLL, in vivo, in vitro.

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How to cite this article:
Groves MJ, MacCallum SF, Boylan MT, Haydock S, Cunningham J, Gelly K, Gowans D, Kerr R, Coates PJ, Tauro S. Heterogeneity of p53-pathway Protein Expression in Chemosensitive Chronic Lymphocytic Leukemia: A Pilot Study. J Cancer 2012; 3:354-361. doi:10.7150/jca.4813. Available from http://www.jcancer.org/v03p0354.htm