P53 Deletion

Although previously difficult to detect, the advent of FISH analysis of interphase cells from patients with B-CLL showed that around 17% of patients with the disease have deletions of the P53 gene¹.

As with ATM, deletions of P53 have important therapeutic implications to patients with B-CLL. Knowledge of the deletion status of P53 in the patient should mediate the choice of therapy. The P53 gene is a tumour suppressor gene and its product, the P53 protein, is responsible for the death of DNA damaged cells thought to be brought about by its phosphorylation and subsequent removal of its inhibition by MDM2 (Mouse Double Minute 2 Homolog). This phosphorylation is mediated by ATM. In the absence of P53 activity, cells that cannot be repaired by ATM will continue to proliferate in their damaged state. Patients deleted for P53 may be rendered resistant to alkylating chemotherapeutic agents as these are designed to damage the DNA in the cells that P53 would have destroyed. In the absence of P53 therefore, patients treated with these agents will harbour a proliferating population of damaged cells.

References:

1. Dohner et al., J Mol Med 1999;77:266-81