Abstract

The TP53 gene located on the short arm of chromosome 17 (17p) encodes p53, which is a transcription factor that regulates the cell cycle and the apoptotic response to genotoxic stress, such as that caused by most anti-cancer drugs. Loss of p53 function in chronic lymphocytic leukemia (CLL) typically is associated with deletions in 17p, which is associated with a poor response to many anti-cancer drugs and poor survival. Although only 5–10% of CLL patients at diagnosis have deletions in 17p by interphase fluorescence in situ hybridization (FISH), the frequency of cases that have 17p- increases in patients with disease that is refractory to chemotherapy. Assays that can screen for loss of p53 function in CLL could help identify patients who most likely will not respond well to most common forms of chemotherapy. Autoantibodies against p53 protein have been observed in several cancers and are, in some cases, linked to p53 protein accumulation in the tumor cells owing to loss of p53-induced expression of the p53-repressor MDM2. We examined the serum samples derived from platelet-free plasma of patients with CLL for anti-p53 autoantibodies by solid-phase ELISA. Anti-p53 autoantibodies were detected in 19 out of 31 plasma samples from patients with known 17p deletions defined by interphase FISH. In contrast, we detected anti-p53 autoantibodies in only 1 out of 27 plasma samples from patients with 11q22–23 deletions and in none of the 29 samples from patients with normal cytogenetics. Detectable levels of soluble p53 protein were identified in only 5 of the 31 patients with 17p deletions, and 3 of those had detectable anti-p53 antibodies. There was no correlation between anti-p53 autoantibody levels and the total plasma IgG. Samples from multiple time points were available for 22 of the patients with 17p deletions. In only one case did the p53 autoantibody status change (from positive to negative). The mechanism that leads to the generation of anti-p53 autoantibodies is unknown. One model suggests that constitutive or over expression of p53 protein by the leukemic cells may lead to a break in tolerance, perhaps if coupled with necrotic or otherwise immunogenic death of the cells. Studies are currently underway to address the status and function of the p53 protein in those patents with high autoantibody levels. This work suggests that auto-antibodies may be useful as a surrogate marker for p53 dysfunction and, more broadly, raises the possibility that auto-antibody profiles may provide clinically relevant insight into the biology and pathophysiology of CLL.

Author notes

Disclosure: No relevant conflicts of interest to declare.