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

Abstract

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.

Roscovitine enhances all-trans retinoic acid (ATRA)-induced nuclear enrichment of an ensemble of activated signaling molecules and augments ATRA-induced myeloid cell differentiation

“…ATRA can induce the proteolytic degradation of this fusion protein resulting in the repression of cell proliferation and induction of myeloid cell differentiation [52]. However, some patients relapse, and disease recurrence is associated with resistance to ATRA [53].…”

Multi-omics and machine learning reveal context-specific gene regulatory activities of PML::RARA in acute promyelocytic leukemia

“…Strikingly, over 40% of differentially expressed, PML::RARA-bound genes were upregulated. Promoter recruitment of PML::RARA has previously been associated with increased transcription of the MYB gene 13 . During the preparation of this manuscript, a report determined that PML::RARA association is required for high expression levels across hundreds of genes in NB4 cells 14 .…”

“…A full catalog of PML::RARA binding partners and their transcriptional effects is incomplete. Intriguingly and in contrast to its known repressive role, PML::RARA has been reported to directly activate MYB gene expression, suggesting divergent consequences of PML::RARA recruitment 13 . Indeed, more recently this non-canonical activity has been suggested to be more widespread 14 .…”

PML Suppresses Influenza Virus Replication by Promoting FBXW7 Expression

“…A few PML proteins, such as PML VIb and PML VIIb, are localized to the cytoplasm due to lack of the nuclear localization signal (NLS). PML, as the major component of PML-NBs, plays important roles in programmed cell death (Hsu and Kao 2018), cell senescence (Li et al 2017), transcriptional regulation (Wang et al 2018), genome stability (Chang et al 2018), and antiviral defense (Blondel et al 2010;Li et al 2009;Alandijany et al 2018;Chen et al 2018;Chelbi-Alix et al 2006;El Asmi et al 2014).…”