CCAAT/enhancer binding protein ε is a potential retinoid target gene in acute promyelocytic leukemia treatment
Dorothy J. Park, … , Wilson H. Miller Jr., H. Phillip Koeffler
Dorothy J. Park, … , Wilson H. Miller Jr., H. Phillip Koeffler
Published May 15, 1999
Citation Information: J Clin Invest. 1999;103(10):1399-1408. https://doi.org/10.1172/JCI2887.
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Article

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.

Authors

Dorothy J. Park, Alexey M. Chumakov, Peter T. Vuong, Doris Y. Chih, Adrian F. Gombart, Wilson H. Miller Jr., H. Phillip Koeffler

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Figure 1

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Induction of C/EBPε expression by retinoid receptor–selective ligands in...
Induction of C/EBPε expression by retinoid receptor–selective ligands in NB4 cells. NB4 cells were incubated with retinoid receptor–selective ligands (5 × 10–7 M) and harvested for total RNA or total cell lysates. (a) Western blot analysis of C/EBPε. NB4 cells were harvested after 2 and 4 days of induction of differentiation. COS-1 cells transfected with either C/EBPε expression vector or empty vector were used as positive (+) and negative (–) controls. Arrows denote C/EBPε. (b) Northern blot analysis for C/EBPε mRNA by hybridization with full-length C/EBPε cDNA probe. The top panel shows the C/EBPε mRNA of 1.2 kb, and the bottom panel shows the ethidium bromide–stained 28S and 18S bands to confirm equivalent loading of RNA.