DEREGULATED EXPRESSION OF THE PU.1 TRANSCRIPTION FACTOR BLOCKS MURINEERYTHROLEUKEMIA CELL TERMINAL DIFFERENTIATION

Murine erythroleukemia (MEL) cells are transformed erythroid precursor s that are blocked from completing the late stages of erythroid differ entiation. A frequent event in the generation of these malignant cells is deregulation of the hematopoietic-specific transcription factor PU .1 (Spi-1) by retroviral insertion of the spleen-focus-forming virus c omponent of Friend virus. During chemically induced reinitiation of ME L cell terminal differentiation, expression of PU.1 is rapidly downreg ulated, suggesting that PU.1 might interfere with processes required f or terminal differentiation of erythroid precursors. To investigate th e role of PU.1 in erythroid differentiation we transfected MEL cells w ith a PU.1 cDNA controlled by the eucaryotic translation elongation fa ctor EF1 alpha promoter. Deregulated expression of PU.1 blocked chemic ally induced differentiation and terminal cell division. Deregulated e xpression of two other protooncogenes, c-myc and c-myb, also has been shown to block MEL differentiation, We present evidence that PU.1 inhi bits terminal differentiation at an earlier step than c-Myc and c-Myb. Thus reinitiation of MEL cell terminal differentiation appears to be controlled by an ordered program of turning off several protooncogenes . Down-regulation of PU.1 may be a very early step in this program.