CCAAT/enhancer binding protein epsilon is a potential retinoid target genein acute promyelocytic leukemia treatment

The CCAAT/enhancer binding protein epsilon (C/EBP epsilon) is a nuclear tra nscription factor expressed predominantly in myeloid cells and implicated a s a potential regulator of myeloid differentiation. We show that it was rap idly induced in the acute promyelocytic leukemia (APL) cell line NB4 during granulocytic differentiation after exposure to retinoic acid (RA), Our dat a suggest that induction of C/EBP epsilon expression was through the retino ic acid receptor alpha (RAR alpha) pathway Reporter gene studies showed tha t C/EBP epsilon promoter/enhancer activity increased in a retinoid-dependen t fashion via the retinoic acid response element (RARE) present in the prom oter region of C/EBP epsilon. The RA-induced expression of C/EBP epsilon ma rkedly increased in U937 myelomonoblasts that were induced to express promy elocytic leukemia/RAR alpha (PML/RAR alpha), but not in those induced to ex press promyelocytic leukemia zinc finger/RAR alpha (PLZF/RAR alpha). In ret inoid-resistant APL cell lines, C/EBP epsilon either is not induced or is i nduced only at very high concentrations of RA (greater than or equal to 10( -6) M). In addition, forced expression of C/EBP epsilon in the U937 myelomo noblastic leukemia cells mimicked terminal granulocytic differentiation, in cluding morphologic changes, increased CD 11b/CD66b expression, and inducti on of secondary granule protein expression. Our data strongly suggest that C/EBP epsilon is a downstream target gene responsible for RA-induced granul ocytic differentiation of APL cells.