p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation

The well-established association between TP53 mutations and adverse clinica l outcome in a range of human cancers reflects the importance of p53 protei n in regulating tumor-cell growth and survival. Although it is theoreticall y possible for p53 dysfunction to arise through mechanisms that do not invo lve TP53 mutation, such a phenomenon has not previously been demonstrated i n a sporadic tumor. Here, we show that p53 dysfunction in B-cell chronic ly mphocytic leukemia (CLL) can occur in the absence of TP53 mutation and that such dysfunction Is associated with mutation of the gene encoding ATM, a k inase implicated in p53 activation. Forty-three patients with CLL were exam ined for p53 dysfunction, as detected by impaired up-regulation of p53 and of the p53-dependent protein p21(ClP1/WAF1) after exposure to ionizing radi ation (IR). Thirty (70%) patients had normal p53 responses and underwent pr ogressive IR-induced apoptosis. In 13 (30%) patients, p21 up-regulation was markedly impaired, indicating p53 dysfunction. Six (14%) of these patients with p53 dysfunction had increased baseline levels of p53, were found to h ave TP53 mutations, and were completely resistant to IR-induced apoptosis. In the other 7 (16%) patients with p53 dysfunction, IR-induced p53 up-regul ation and apoptosis were markedly impaired, but baseline levels of p53 were not Increased, and no TP53 mutations were detected. Each of these patients was found to have at least one ATM mutation, and a variable reduction in A TM protein was detected in all 4 patients examined. This Is the first study to provide a direct demonstration that p53 dysfunction can arise In a spor adic tumor by a mechanism that does not involve TP53 mutation. (C) 2001 by The American Society of Hematology.