RETROVIRAL TRANSDUCTION OF HEMATOPOIETIC PROGENITOR CELLS WITH MUTANTP53 PROMOTES SURVIVAL AND PROLIFERATION, MODIFIES DIFFERENTIATION POTENTIAL AND INHIBITS APOPTOSIS

Mutations in the p53 tumor suppressor gene have been shown to be assoc iated with many human tumors and various leukemias and lymphomas. To e xamine whether constitutive overexpression of mutant p53 can effect tr ansformation of normal hematopoietic cells, a mutant p53 gene was intr oduced into normal murine bone marrow hematopoietic cells by retrovira l gene transfer. Compared to vector alone-infected cells, hematopoieti c progenitor cells transduced with mutant p53 showed increased prolife rative potential, enhanced cloning efficiencies and a modified differe ntiation pattern in vitro. In addition, mutant p53-transduced hematopo ietic cells were more resistant to loss of viability and/or induction of apoptosis when cultured in a low concentration of serum or in the a bsence of both growth factors and serum. These effects occurred rapidl y with no apparent contributory secondary events. No permanent cell li nes or growth factor-independent cell strains were obtained. The resul ts indicate that introduction of mutant p53 into normal hematopoietic cells in vitro contributes to transformation, including enhanced proli ferative potential, modified differentiation and the suppression of ap optosis in these cells.