ANTIAPOPTOTIC EFFECT OF C-FES PROTOONCOGENE DURING GRANULOCYTIC DIFFERENTIATION

The c-fes protooncogene is expressed at high levels in the terminal st ages of granulocytic differentiation. Its product, p92(c-fes), exhibit s a tyrosine-kinase activity and is involved in the cellular response to GM-CSF, but its role is not yet clarified. To study this problem, t he c-fes protooncogene expression has been inhibited in HL60 cells and in fresh leukemic blast cells of Acute Promyelocylic Leukemia (APL) i nduced to differentiate with All-Trans-Retinoic Acid (ATRA). Inhibitio n of c-fes function was obtained by treatment of the cells with a spec ific antisense oligomer complementary to the 5' region of the c-fes mR NA. It was observed that the cells, rather then differentiate to granu locytes, underwent premature cell death showing the morphological and molecular characteristics of apoptosis. Superimposable results are obt ained on blast cells from APL. It is possible to conclude that the los s of cell viability that occurs during the in vitro differentiation of myeloid cells, after the complete inhibition of c-fes expression and treatment with ATRA, is due to activation of programmed cell death rat her than an accelerated differentiation. Our data suggest that the c-f es product is essential for the survival of myeloid cells during diffe rentiation.