No abstract

CCAAT/enhancer binding proteins (C/ EBPs) are a family of factors that regulate cell growth and differentiation. These factors, particularly C/EBP␣ and C/EBP⑀, have important roles in normal myelopoiesis. In addition, loss of C/EBP activity appears to have a role in the pathogenesis of myeloid disorders including acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL) is a subtype of AML in which a role for C/EBPs has been postulated. In almost all cases of APL, a promyelocytic leukemia-retinoic acid receptor ␣ (PML-RAR␣) fusion protein is expressed as a result of a t(15;17)(q22; q12) chromosomal translocation. PML-RAR␣ inhibits expression of C/EBP⑀, whereas all-trans retinoic acid (tRA), a differentiating agent to which APL is particularly susceptible, induces C/EBP⑀ expression. PML-RAR␣ may also inhibit C/EBP␣ activity. Thus, the effects of PML-RAR␣ on C/EBPs may contribute to both the development of leukemia and the unique sensitivity of APL to tRA. We tested the hypothesis that increasing the activity of C/EBPs would revert the leukemic phenotype. C/EBP␣ and C/EBP⑀ were introduced into the FDC-P1 myeloid cell line and into leukemic cells from PML-RARA transgenic mice. C/EBP factors suppressed growth and induced partial differentiation in vitro. In vivo, enhanced expression of C/EBPs prolonged survival. By using a tamoxifen-responsive version of C/EBP⑀, we observed that C/EBP⑀ could mimic the effect of tRA, driving neutrophilic differentiation in leukemic animals. Our results support the hypothesis that induction of C/EBP activity is a critical effect of tRA in APL. Furthermore, our findings suggest that targeted modulation of C/EBP activities could provide a new approach to therapy of