Functional assessment of p53 in chronic lymphocytic leukemia

Several prognostic factors are used in chronic lymphocytic leukemia (CLL) to predict disease progression at diagnosis and to help guide therapeutic choices. Among these factors, the detection of deletions of the short arm of chromosome 17, where the tumor suppressor gene TP53 is located at the 17p13 locus, predicts resistance to standard treatments and poor prognosis. Deletions of 17p13 are observed in 5–7% of CLL patients at diagnosis and in 25–40% of cases with advanced refractory disease. Other markers of poor prognosis have been described, such as unmutated IGHV gene status, high levels of thymidine kinase and soluble CD23, CD38 and ZAP-70 expression, as well as other chromosomal aberrations, such as 11q23 deletion. However, defects in the TP53 pathway consistently appear as the most significant adverse prognostic factor in CLL. About 80% of patients with 17p13 deletion display a mutation in the remaining TP53 allele, resulting in loss of function of the p53 protein, but mutations without a deletion are observed in 4–5% of cases. Mutations of TP53 have been identified that are consequently associated with an unfavorable outcome, but all mutations do not predict similar consequences on the p53 pathway. In addition, a minority of patients with 17p13 deletion have an indolent clinical course, suggesting that p53 function is preserved. Finally, it has appeared that p53 dysfunction is the result of several intricate factors that have not been clearly defined, and several questions still remain to be addressed regarding the biological consequences of TP53 deletions and the various types of mutations. Consequently, it has become evident that new techniques to determine p53 function are required to identify patients with TP53 abnormalities (deletion and/or mutation), despite normal function, and patients who have TP53 neither mutated nor deleted, but which is dysfunctional for other reasons, including