Functional p53 is required for rapid restoration of daunorubicin-induced lesions of the spleen

Abstract

Background: The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen. Methods: Mice with wild type or deleted Trp53 were treated with the daunorubicin (DNR) for three consecutive days. Spleens were collected at various time points after treatment, and examined for signs of chemotherapyrelated lesions by microscopic analysis of haematoxylin-eosin or tunel-stained paraffin sections. Expression of deathinducing proteins was analysed by immunoblotting. Changes between Trp53 wild type and null mice were compared by t-tests. Results: Signs of cell death (pyknotic nuclei and tunel-positive cells) in the white pulp of the spleen occurred earlier following DNR exposure in wt-mice compared to Trp53-null mice. While the spleen of wt-mice recovered to normal morphology, the spleen of the Trp53-null animals still had lesions with large necrotic areas and disorganised histologic appearance eight days after treatment. Immunoblotting showed that only Trp53-wt mice had significant increase in p21 after DNR treatment. However, both wt and null mice had elevated p63 levels following DNR exposure. Conclusions: p53 protects against severe and enduring cellular damage of the spleen parenchyma after DNR treatment, and initial DNR-induced apoptosis is not predictive of tissue lesions in the spleen. Our data indicate that p53 induction following DNR treatment serves to protect rather than to destroy normal tissue.