DISTINCT EFFECTS OF VARIOUS P53 MUTANTS ON DIFFERENTIATION AND VIABILITY OF HUMAN K562 LEUKEMIA-CELLS

Mutations of the p53 tumor suppressor are often observed in various hu man tumors, including blast crisis of chronic myelogenous leukemia (CM L). The pattern of p53 mutations in CML shows some peculiarities compa red with majority of other malignancies. In particular, the substituti ons at codon 273, one of the most common p53 alterations in various tu mors, are not characteristic of CML. To test whether the distinctions in the pattern of p53 mutations are connected with some peculiarities of the biological effects of different mutant proteins in leukemic cel ls, we obtained and analyzed a panel of human K562 cell sublines expre ssing various exogenous p53: human Pro156, His175, His194, Trp248, and His273, or murine temperature-sensitive (ts) Val135 that has properti es of mutant protein at 37 degrees C, but shows activities of the wild -type (wt) p53 at 32 degrees C. We have found that expression of wt-p5 3 enhanced the dependence of cells on growth/survival factors. Incubat ion of sparse (< 10(5) cells per/ml) K562/Val135 cultures at 32 degree s C caused apoptosis. In media conditioned by cells of different origi n (K562, colorectal carcinoma LIM1215, Rat1 fibroblasts) the p53-depen dent apoptosis was inhibited. Under such conditions the expression of ts-wt-p53 was accompanied by dramatic increase in the number of cells producing specific markers of erythroid differentiation - GlycPhA and Ag-Eb. Unlike to the wt-p53, the majority of tumor-derived mutant p53 (Pro156, His175, His194) increased cell survival in low serum and decr eased the number of cells expressing GlycPhA, CD9, CD15, and CD71 diff erentiation antigens. On the other hand, expression of His273-p53 caus ed significant augmentation in the number of CD9-positive cells and en hanced the dependence on growth/survival factors that are present in s erum or conditioned media. The data obtained allow to suggest that an unusual pattern of p53 mutations in CML reflects some peculiarities of biological effects of certain mutant proteins on differentiation and viability of leukemic cells.