CCAAT/enhancer binding protein ε is a potential retinoid target gene in acute promyelocytic leukemia treatment

Abstract

The CCAAT/enhancer binding protein ε (C/EBPε) is a nuclear transcription factor expressed predominantly in myeloid cells and implicated as a potential regulator of myeloid differentiation. We show that it was rapidly induced in the acute promyelocytic leukemia (APL) cell line NB4 during granulocytic differentiation after exposure to retinoic acid (RA). Our data suggest that induction of C/EBPε expression was through the retinoic acid receptor α (RARα) pathway. Reporter gene studies showed that C/EBPε promoter/enhancer activity increased in a retinoid-dependent fashion via the retinoic acid response element (RARE) present in the promoter region of C/EBPε. The RA-induced expression of C/EBPε markedly increased in U937 myelomonoblasts that were induced to express promyelocytic leukemia/RARα (PML/RARα), but not in those induced to express promyelocytic leukemia zinc finger/RARα (PLZF/RARα). In retinoid-resistant APL cell lines, C/EBPε either is not induced or is induced only at very high concentrations of RA (≥10 -6 M). In addition, forced expression of C/EBPε in the U937 myelomonoblastic leukemia cells mimicked terminal granulocytic differentiation, including morphologic changes, increased CD11b/CD66b expression, and induction of secondary granule protein expression. Our data strongly suggest that C/EBPε is a downstream target gene responsible for RA-induced granulocytic differentiation of APL cells.

Common themes in the pathogenesis of acute myeloid leukemia

“…Another recently identi®ed target of RARa is the transcription factor C/ EBPe, a member of the C/EBP family preferentially expressed in myeloid cells. Forced expression of C/ EBPe in U937 cells mimics terminal granulocytic di erentiation, including morphologic changes, increased CD11b/CD66b expression, and induction of secondary granule protein expression (Park et al, 1999). The cdk-inhibitor p21 is also a direct target of RARa, and its transcription is strongly induced during di erentiation of U937 cells treated with RA (Liu et al, 1996a).…”

Transcriptional regulation of granulocyte and monocyte development

“…Indeed, as with C/EBPa, C/EBPb, C/EBPd, or C/EBPe can induce granulocytic di erentiation in myeloblastic cell lines (Park et al, 1999;Nakajima and Ihle, 2001;Wang and Friedman, 2002), and C/EBPa, C/EBPb, or C/EBPd induced monocytic genes in P388 lymphoblasts (Hu et al, 1998). Redundancy is also evident from the ability of C/EBPb to compensate for the loss of C/EBPa in hepatocytes and granulocytes in vivo (Chen et al, 2000;Jones et al, 2002).…”

Identification of murine and human XCP1 genes as C/EBP-ε-dependent members of FIZZ/Resistin gene family

“…The expression pattern of hXCP1 was thus identical to that of C/EBP-e in normal human tissues, while the expression of hXCP2 closely resembled that of murine XCP3/FIZZ2 gene. C/EBP-e is strongly upregulated following treatment with 9-cis retinoic acid (RA) in NB4 cells Park et al, 1999). We used an hXCP1 probe to analyse mRNA of NB4 cells prior to and after RA treatment and in several other cell lines with a known expression pattern of C/EBP-e ( Figure 4b).…”