Activation ofG0S2is coordinated by recruitment of PML/RARα and C/EBPε to its promoter during ATRA-induced APL differentiation.
All-transretinoic 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 (G0S2) during ATRA-induced neutrophil differentiation of leukemia cell lines (NB4 and PR9) and primary human APL cells. C/EBPε occupancy of theG0S2promoter 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 ofG0S2and that PML/RARα interacts physically and cooperates functionally with C/EBPε to up-regulateG0S2Our 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 targetG0S2, thereby contributing to ATRA-mediated APL differentiation and potentially, clinical remission.
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
Fang
F
Zhang
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
Yong Lan
YL
Zhu
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
Wang Long
WL
Deng
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
Jiang
J
Zhu
State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China; and hematology_sjtu@163.com jizhang@sibs.ac.cn.|Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, Shanghai, China.
Ji
J
Zhang
D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology*; D008024:Ligands; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; C508073:G0S2 protein, human; D008024:Ligands; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070790:CEBPE protein, human; D014212:Tretinoin
G0/G1 switch gene 2; acute promyelocytic leukemia; all-trans retinoic acid; neutrophil