Leukemogenesis is controlled by a number of transcription factors regulating the expression of essential genes, including human neutrophil elastase (HNE). Herein, we have investigated activity of the transcription factor PU.1 as a major regulator of myeloid development in association with modulated cell differentiation by protein kinase inhibitors. We have demonstrated that PU.1 binding activity to the HNE promoter is associated with retinoic acid (RA)-induced maturation of acute promyelocytic leukemia (APL) HL-60 cells and blasts from APL patients. Blocking of conventional protein kinase C isozymes increased PU.1 activity and total protein tyrosine phosphorylation during cell maturation to granulocytes. Inhibition of tyrosine protein kinase suppressed cell differentiation and PU.1 activity in differentiating cells. In summary, our results demonstrate the importance of the PU.1 regulating HNE gene promoter for HL-60 cell differentiation via phosphorylation.

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