MDM2 OVEREXPRESSION DOES NOT ACCOUNT FOR STABILIZATION OF WILD-TYPE P53 PROTEIN IN NON-HODGKINS-LYMPHOMAS

p53 protein overexpression is a frequent finding in non-Hodgkin's lymp homas (NHL), being detected in over 25% of the cases, Moreover, some h igh-grade lymphomas and a large fraction of low-grade tumors show a pa ttern of scattered p53 accumulation in a limited percentage of neoplas tic cells, In contrast, NHLs show a low frequency of p53 gene mutation s. To investigate the molecular bases of p53 protein overexpression, a large series of NHLs was analyzed for p53 gene status, The analysis o f the entire coding region of the gene (exons 2-11) and corresponding donor and acceptor splicing sites indicated that a significant proport ion of p53-positive tumors overexpresses a wild-type form of p53 prote in (wt-p53), To assess whether wt-p53 accumulation was related to the formation of inactive complexes with endogenous proteins, MDM2 oncogen e expression and amplification were analyzed, MDM2 overexpression was detected only in one third of the wt-p53-positive cases, thus excludin g that MDM2 accounts tout court for the accumulation of a normal p53 p rotein. However, the fact that MDM2 overexpression was detected in onl y the p53-positive cases and the observation that MDM2-positive cells were a subpopulation of p53-positive cells suggest a link between the two phenomena. In particular, our results indicate that the accumulati on of a wt form of p53 protein could promote the overexpression of the MDM2 gene product. In addition, the prevalence of MDM2 positivity in intermediate/high-grade tumors together with the concordant expression of wt-p53 and MDM2 only in the high-grade component of a 'composite' lymphoma suggests that perturbation in the MDM2/p53 critical ratio cou ld play a role in lymphoma progression. (C) 1995 by The American Socie ty of Hematology.