ArticleProceedings of the National Academy of Sciences of the United States of America2024
Phase separation of PML/RARα and BRD4 coassembled microspeckles governs transcriptional dysregulation in acute promyelocytic leukemia.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Retinoic acid in health and disease.Signal transduction and targeted therapy · 2026Review
- Condensates in fusion oncoprotein-driven leukemia: new biology and therapeutic opportunities.Trends in cancer · 2026Review
- TCEA1 Suppresses Acute Promyelocytic Leukemia by Upregulating C/EBPε and IRF8.International journal of molecular sciences · 2026Article
- Epigenetically controlled endothelial promyelocytic leukemia drives liver inflammation and fibrosis.The Journal of clinical investigation · 2026Article
- Liquid-liquid phase separation-driven regulated cell death: from molecular mechanisms to therapeutic strategies.Cell death discovery · 2026Review
- Atypical singleBlood neoplasia · 2026Article
- Liquid-Liquid Phase Separation in Cancer Drug Resistance: Mechanisms and Therapeutic Opportunities.Oncology research · 2026Review
- Super-enhancer-associated long noncoding RNA lnc-SPI1U mediates SPI1 feedback regulation by interacting with HNRNPH1 and HNRNPF.Oncogene · 2025Article
- A Microfluidic Platform for Actin-Based Membrane Remodeling Reveals the Stabilizing Role of Branched Actin Networks on Lipid Microdomains.Small science · 2025Article
- Intrinsically Disordered Regions of Zinc Finger Protein 687 in Phase Separation: A Potentially Pathogenic Driver of Paget's Disease of Bone.ACS pharmacology & translational science · 2025Review
- Biomolecular phase separation in tumorigenesis: from aberrant condensates to therapeutic vulnerabilities.Molecular cancer · 2025Review
- Liquid-liquid phase separation in normal hematopoiesis and hematological diseases.Cell and tissue research · 2025Review
- Biomolecular condensates in immune cell fate.Nature reviews. Immunology · 2025Review
- Super-enhancer-associated LINC00963 promotes metastasis of gastric cancer through epithelial-mesenchymal transition.PloS one · 2025Article
- Liquid-liquid phase separation in super enhancer-driven oncogenesis: mechanisms, immune evasion, and therapeutic implications.Frontiers in cell and developmental biology · 2025Review
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14 authors.
Funding
Abstract
In acute promyelocytic leukemia (APL), the promyelocytic leukemia-retinoic acid receptor alpha (PML/RARα) fusion protein destroys PML nuclear bodies (NBs), leading to the formation of microspeckles. However, our understanding, largely learned from morphological observations, lacks insight into the mechanisms behind PML/RARα-mediated microspeckle formation and its role in APL leukemogenesis. This study presents evidence uncovering liquid-liquid phase separation (LLPS) as a key mechanism in the formation of PML/RARα-mediated microspeckles. This process is facilitated by the intrinsically disordered region containing a large portion of PML and a smaller segment of RARα. We demonstrate the coassembly of bromodomain-containing protein 4 (BRD4) within PML/RARα-mediated condensates, differing from wild-type PML-formed NBs. In the absence of PML/RARα, PML NBs and BRD4 puncta exist as two independent phases, but the presence of PML/RARα disrupts PML NBs and redistributes PML and BRD4 into a distinct phase, forming PML/RARα-assembled microspeckles. Genome-wide profiling reveals a PML/RARα-induced BRD4 redistribution across the genome, with preferential binding to super-enhancers and broad-promoters (SEBPs). Mechanistically, BRD4 is recruited by PML/RARα into nuclear condensates, facilitating BRD4 chromatin binding to exert transcriptional activation essential for APL survival. Perturbing LLPS through chemical inhibition (1, 6-hexanediol) significantly reduces chromatin co-occupancy of PML/RARα and BRD4, attenuating their target gene activation. Finally, a series of experimental validations in primary APL patient samples confirm that PML/RARα forms microspeckles through condensates, recruits BRD4 to coassemble condensates, and co-occupies SEBP regions. Our findings elucidate the biophysical, pathological, and transcriptional dynamics of PML/RARα-assembled microspeckles, underscoring the importance of BRD4 in mediating transcriptional activation that enables PML/RARα to initiate APL.
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