INHIBITION OF C-FES EXPRESSION BY AN ANTISENSE OLIGOMER CAUSES APOPTOSIS OF HL-60 CELLS INDUCED TO GRANULOCYTIC DIFFERENTIATION

The c-fes protooncogene is expressed at high levels in the terminal st ages of granulocytic differentiation, but so far no definite function has been attributed to the product of this oncogene. To tackle this pr oblem, the c-fes protooncogene expression has been inhibited in HL60 c ells, and fresh leukemic promyelocytes of acute promyelocytic leukemia have been induced to differentiate with retinoic acid (RA) and dimeth ylsulfoxide (DMSO). Inhibition was obtained by incubating the cells wi th a specific c-fes antisense oligodeoxynucleotide. It was observed th at the cells, rather than differentiating, underwent premature cell de ath showing the morphological and molecular characteristics of apoptos is. This process was inhibited by granulocyte and granulocyte/macropha ge colony-stimulating factor, but not by interleukin 3 (IL-3), IL-6, o r stem cell factor. Our present results demonstrate that the loss of c ell viability that occurs during the in vitro differentiation of myelo id cells, after the complete inhibition of the c-fes gene product and treatment with RA-DMSO, is due to activation of programmed cell death. It is concluded that a possible role of the c-fes gene product is to exert an antiapoptotic effect during granulocytic differentiation.