PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms

The promyelocytic leukemia (PML)/retinoic acid receptor‐alpha (RARα) onco‐fusion protein that is generated from t(15;17) chromosome translocation is crucial for the leukemogenesis of acute promyelocytic leukemia (APL) and is well documented as a transcriptional repressor. To understand the relationship between PML/RARα and the oncogene in the development of APL, we investigate the regulation mechanism of PML/RARα to MYB proto‐oncogene and the role of this regulation on the proliferation and differentiation of APL cells. Reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) assays show that MYB expression was significantly higher in PML/RARα positive cell lines. Microarray data verify that the MYB expression was significantly higher in APL patient samples than in normal promyelocyte samples. Further expression analysis from RT‐qPCR and microarray data verifies that the expression of MYB is upregulated by PML/RARα. Transcriptional factor binding analysis shows that MYB is directly bound by PML/RARα and its cofactors. Luciferase assays show that PML/RARα transactivated MYB promoter activity through the RARα binding site and the coexistence of CCAAT enhancer binding protein ε. We also find that PML/RARα increases the acetylation level of the promoter region of MYB. Further evidence demonstrates that PML/RARα regulates MYB expression through long‐range interaction. Functionally, PML/RARα increases the cell proliferation and blocks the differentiation through activating MYB expression. Collectively, this study uncovers a novel mechanism of PML/RARα‐mediated transcriptional activation and enriches our knowledge of the onco‐fusion protein‐mediated transcription activation. In this study, we examined the transcriptional activation mechanism of promyelocytic leukemia (PML)/retinoic acid receptor‐α (RAR) to its target gene, MYB. We found that the activation was mediated by both transcriptional and epigenetic regulatory mechanisms. Functionally, PML/RAR increases the cell proliferation and blocks the differentiation through activating MYB expression. Collectively, this study uncovers a novel mechanism of PML/RAR‐mediated transcriptional activation and enriches our knowledge of the onco‐fusion protein‐mediated transcription activation.