A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARα and PML/RARα. [RNA-Seq]
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PROVIDER: PRJNA802138 | ENA |
REPOSITORIES: ENA
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Project description:A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARα and PML/RARα.
| PRJNA802131 | ENA
Project description:Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia development is obscure. Here, we conducted a retrospective study containing 1,412 medical records (319 APL, 393 non-APL acute myeloid leukemia (AML), and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non-APL AML and non-tumor controls. We revealed that triglyceride served as a risk factor of early death in APL patients, and there was a positive correlation between high triglyceride levels and high leukocyte counts. RNA-seq analysis on APL patients with high or normal triglyceride levels brought attention to peroxisome proliferator-activated receptor-alpha (PPARα) signaling, a crucial regulator of cell metabolism and a transcription factor involved in cancer development. We demonstrated that PPARα knockdown inhibited the proliferation of APL cells. Chromatin mapping data analysis with CUT&Tag revealed that PPARα coexisted with PML/RARα within the super-enhancer regions to maintain APL. Interventions to PPARα affected the transcription and protein level of FLT3. Moreover, in vivo results in mice having high-fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemia burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL cell proliferation and high triglyceride levels and established the contribution of an hyperlipidemia–PPARα–FLT3 axis to APL development.
2022-11-02 | GSE195777 | GEO
Project description:Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia development is obscure. Here, we conducted a retrospective study containing 1,412 medical records (319 APL, 393 non-APL acute myeloid leukemia (AML), and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non-APL AML and non-tumor controls. We revealed that triglyceride served as a risk factor of early death in APL patients, and there was a positive correlation between high triglyceride levels and high leukocyte counts. RNA-seq analysis on APL patients with high or normal triglyceride levels brought attention to peroxisome proliferator-activated receptor-alpha (PPARα) signaling, a crucial regulator of cell metabolism and a transcription factor involved in cancer development. We demonstrated that PPARα knockdown inhibited the proliferation of APL cells. Chromatin mapping data analysis with CUT&Tag revealed that PPARα coexisted with PML/RARα within the super-enhancer regions to maintain APL. Interventions to PPARα affected the transcription and protein level of FLT3. Moreover, in vivo results in mice having high-fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemia burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL cell proliferation and high triglyceride levels and established the contribution of an hyperlipidemia–PPARα–FLT3 axis to APL development.
2022-11-02 | GSE195776 | GEO
Project description:A novel interplay between triglycerides and acute promyelocytic leukemia mediated by the cooperation between PPARα and PML/RARα. [CUT&Tag]
| PRJNA802139 | ENA
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 unclear. Here, we performed the genome-wide binding profiling of PML/RARα and BRD4 in NB4, an APL patient-derived cell line. Moreover, we also performed ChIP-seq of PML/RARα and BRD4 upon genetic or pharmacological pertubation of PML/RARα or BRD4 to determine how they target regulatory elements.
2024-12-31 | GSE261292 | GEO
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 mechanism underlying PML/RARα mediated transcriptional dysregulation remain unclear. Here, we performed the transcription profiling in NB4, an APL patient-derived cell line.
2024-12-31 | GSE261293 | GEO
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:This SuperSeries is composed of the SubSeries listed below.
2022-11-02 | GSE195779 | GEO
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: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