Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA234436 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia. DNA methylation profiling in CD34(+) early promyelocytes and CD34(-) late promyelocytes cells from PML-RARa transgenic mice vs. control mice.
2015-09-04 | E-GEOD-54038 | biostudies-arrayexpress
Project description:Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia.
2015-09-04 | GSE54038 | GEO
Project description:A global view of PML-RARα transcriptional functions was obtained by genome-wide binding and chromatin modification analyses, combined with genome wide expression data. Complete Abstract: The translocation t(15;17) generates the chimeric PML-RARα transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RARα transcriptional functions was obtained by genome-wide binding and chromatin modification analyses, combined with genome wide expression data. ChIP-chip experiments identified 372 direct genomic PML-RARα targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RARá targets include regulators of global transcriptional programs as well as critical regulatory genes for basic cellular functions such as cell cycle control and apoptosis. PML-RARα binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased tri-methylation of histone H3 lysine 9 and unexpectedly increased tri-methylation of histone H3 lysine 4. The binding of PMLRARα to target promoters and the resulting histone modifications resulted in mRNA repression of functionally relevant genes. Taken together our results reveal that the transcription factor PML-RARα regulates key cancer related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes. Keywords: ChIP on Chip
2008-09-06 | GSE12641 | GEO
Project description:We defined the RARα interactome in the MDA-MB453 breast cancer cell line genetically engineered to over-express an N-terminally tagged version of the nuclear retinoic acid receptor. Twenty eight nuclear proteins which interact with RARα and whose interaction is stimulated or reduced by the pan-RAR ligand, all-trans retinoic acid (ATRA) were identified. Given the potential significance of the S100A3 calcium-binding protein in the control of tumor progression, we focused our attention on this factor. Using the two models represented by the ATRA-sensitive SKBR3 and MCF7 breast cancer cell lines characterized by constitutive expression of S100A3 and RARα, we demonstrate that the endogenous forms of S100A3 and RARα interact in physiological conditions. The interaction of S100A3 with RARα is cell context independent and it is observed not only in breast cancer but also in acute promyelocytioc leukemia (APL) cells, characterized by expression of the RARα-derived PML-RARα oncogene, which is the product of the t(15:17) chromosomal translocation. S100A3 interacts directly and specifically with RARα and PML-RARα, being unable to bind other members of the RAR/RXR family of retinoid nuclear receptors. The interaction surface maps to the carboxyl-terminal region of the RARα ligand binding domain. Binding of S100A3 to RARα and PML-RARα controls the constitutive and ATRA-dependent degradation of the two receptors. Silencing of the S100A3 gene decreases the amounts of RARα in breast SK-BR-3 and lung A549 cancer cells, rendering them more refractory to the anti-proliferative action of ATRA. In SK-BR-3 cells, this effect is accompanied by a decrease in the lactogenic/differentiating action of ATRA. In APL-derived NB4 cells, S100A3 knock-down reduces the amounts of both RARα and PML-RARα. Contemporaneous down-regulation of the two receptors is associated with an increase in the basal and ATRA-induced expression of many granulocytic differentiation markers. Opposite on RARα and PML-RARα levels as well as ATRA induced differentiation markers are observed upon over-expression of S100A3 in NB4 cells.
2019-12-18 | PXD008761 | Pride
Project description:Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosome translocation that generates the promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion gene. However, the global association between PML/RARα and transcriptional co-regulators, and the rules of their association in governing the key processes during the leukemogenesis remain obscure. Here, we performed the genome-wide binding profiling of PML/RARα, HDAC1 and P300, in NB4, an APL patient-derived cell line. We found that PML/RARα targets could be classified into two classes. Moreover, we also performed ChIP-seq of H3K27ac to determine super-enhancers in NB4. We identified a novel function of PML/RARα in super-enhancer regulation during the leukemogenesis of APL.
2020-08-26 | GSE126720 | GEO
Project description:Transcriptional profiling of murine cells expressing PML/RARA at the early promyelocyte stage (4 weeks old, preleukemic) and in full blown PML/RARA leukemia generated by transducing PML/RARA bone marrow with a Flt3-ITD retroviral vector Two-conditions experiment: preleukemic early promyelocytes vs leukemic promyelocytes
2015-07-15 | E-GEOD-59431 | biostudies-arrayexpress
Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.
2019-12-17 | GSE142198 | GEO
Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.
2019-12-17 | GSE142197 | GEO
Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.
2019-12-05 | GSE137661 | GEO
Project description:ATO is a therapeutic agents used to treat APL, a disease caused by a chromosomal translocation of the RARα gene that can occur reciprocally with the PML gene. The mechanisms through which ATO function and how increased levels of ATO adversely affect the cell are not fully characterized though they involve the SUMOylation, the ubiquitylation and the degradation of the PML/RARα oncoprotein through the PML moiety. Changes in protein SUMOylation, phosphorylation and ubiquitylation were profiled using large-scale proteomic workflows on HEK293 cells following exposure to typical (1 μM) or elevated (10 μM) ATO for 4h to understand the mechanism that underlies the cytotoxicity induced with important ATO levels. Our analyses revealed that 88 proteins displayed divergent SUMOylation with elevated ATO compared to the lower dose, where the latter caused changes in SUMOylation of 4 proteins, including PML. Some of these differing SUMOylation events occurred on known substrates of caspase-3. A similar phenomenon was observed in the phosphoproteomic studies, where 48 proteins were specifically regulated with elevated ATO levels, while low ATO doses barely altered the phosphoproteome. Elevated levels of ATO cause the erroneous SUMOylation and phosphorylation of a vast amount of substrates, which may be responsible for its cytotoxic effects.
2020-04-06 | PXD016166 | Pride