p53 in hematologic malignancies.

T HE p53 HAS BEEN CHOSEN as molecule of the year for 1993 by the journal Science.' The protein's illustrious history began quietly in 1979, when a 53-kD eukaryotic protein was shown to bind to SV40 large T The protein was named p53 because of its size. Initial studies suggested that p53 was an oncogene because it could transform rodent ~ e l l s . ~ ' ~ The p53 genes used in these studies had been isolated from cancer cell lines; these p53 genes were subsequently discovered to contain missense mutations and the resultant mutant proteins had properties different from those of wild-type (wt) ~ 5 3 . ' . ' ~ " ~ Investigators also noted that several virally transformed murine cell lines as well as a human myeloid leukemic cell line (HL-60) had major deletions of the p53 gene.",'" We found that the p53 gene was mutated in human cancer; four of five osteosarcomas from patients had major disruptions of their p53 genes." Other studies found that loss of heterozygosity (LOH) of the short arm of human chromosome 17 in the region coding for p53 occurred in a number of human cancers.22-24 Additional careful analysis of the p53 gene has shown that it is frequently mutated in more than 50 varieties of human cancers including lung, breast, thyroid, gastrointestinal, and ovarian cancers, lymphomas/leukemias, and brain tumors.2',2s-44 Further functional studies determined that wt-p53 suppressed transformation of cells's"s and overexpression of wt-p53 blocked cells in the G , phase of the cell cycle.J',46 Taken together, p53 fulfills the criteria of a tumor-suppressor gene, including the finding of LOH in the region of p53 in tumors, the presence of p53 mutations in human and murine tumors and transformed cell lines, and the ability of wt-p53 to suppress transformation of cells having p53 mutations. In one decade, a protein discovered through an effort to understand how SV40 transforms cells was initially characterized as an oncogene, only to find that it is a pivotal tumor-suppressor that is the guardian of DNA-damaged cells by halting their proliferation, pushing badly damaged cells into an apoptotic cell death and preventing unwanted DNA amplification. This review will characterize the p53 abnormalities in hematopoietic malignancies and discuss the clinical significance of these alterations. In addition, potential therapeutic approaches will be briefly mentioned.