Activation of G0S2 is coordinated by recruitment of PML/RARα and C/EBPε to its promoter during ATRA-induced APL differentiation

• Published in: Journal of leukocyte biology Vol. 101; no. 3; pp. 655 - 664
• Main Authors: Zhang, Fang, Zhu, Yong Lan, Deng, Wang Long, Zhu, Jiang, Zhang, Ji
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2017
• Subjects: Acute promyeloid leukemia; Base Sequence; CCAAT-Enhancer-Binding Proteins - metabolism; Cell activation; Cell Cycle Proteins - metabolism; Cell Differentiation - drug effects; Cell Line, Tumor; Chromatin; Deoxyribonucleic acid; Differentiation; DNA; Fusion protein; Humans; Immunoprecipitation; Leukemia; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - pathology; Ligands; Mode of action; Oncogene Proteins, Fusion - metabolism; Promoter Regions, Genetic; Promyeloid leukemia; Protein Binding - drug effects; Remission; Retinoic acid; Transcription; Transcriptional Activation - genetics; Tretinoin; Tretinoin - pharmacology; Tumor cell lines; G0/G1 switch gene 2; all-trans retinoic acid; acute promyelocytic leukemia; neutrophil
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.1A0316-116R

All- retinoic acid (ATRA) binds the promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion protein and is an effective oncogene-targeted therapy for acute promyelocytic leukemia (APL). However, the molecular basis of PML/RARα-mediated transcriptional control during ATRA-induced differentiation is unclear. Previous studies have shown that the PML/RARα fusion protein behaves as a type II nuclear receptor, binding to DNA regardless of ligand status. Here, we performed a series of chromatin immunoprecipitation (ChIP)-quantitative PCR (qPCR) experiments, demonstrating that there is an additional mode of action of PML/RARα, wherein PML/RARα does not bind DNA in the absence of ATRA but binds DNA and activates adjacent genes in the presence of ATRA. This mode of action is similar to that of a type I nuclear receptor and is highlighted by activation of G0/G1 switch gene 2 ( ) during ATRA-induced neutrophil differentiation of leukemia cell lines (NB4 and PR9) and primary human APL cells. C/EBPε occupancy of the promoter was elevated in parallel with recruitment of PML/RARα in ATRA-treated NB4, PR9, and primary APL cells. Furthermore, we verified that the p30 isoform of C/EBPε is crucial for activation of and that PML/RARα interacts physically and cooperates functionally with C/EBPε to up-regulate Our data not only demonstrate a new mode of action of PML/RARα but also suggest a novel model in which PML/RARα synergizes with C/EBPε to reactivate the C/EBPε target , thereby contributing to ATRA-mediated APL differentiation and potentially, clinical remission.