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Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9

ABSTRACT: Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9

PROVIDER: PRJNA589270 | ENA |

REPOSITORIES: ENA

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Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [array]

Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits E3 ubiquitin ligase COP1 to C/EBPa, and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 has been observed in myeloid leukemogenesis as Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. Yet the mechanism how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Here we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analyses identified increased Histone H3K27Ac signals at the super-enhancers such as Erg, Aff3, Spns2 and Coro2 loci, as well as increased mRNA expression of these genes. The modification of super-enhancer activities is mostly achieved by degradation of C/EBPa by Trib1 and the MEK/ERK pathway only slightly contributes to the activities. Silencing of Erg abrogates the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of AML cells with the BRD4 inhibitor JQ1 showed growth inhibition in the Trib1/Erg-dependent manner. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential target of Hoxa9-associated AML. We used microarrays to detail the global program of gene expression in mouse AML

2020-10-21 | GSE139641 | GEO

Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [ChIP-seq]

Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits E3 ubiquitin ligase COP1 to C/EBP, and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 has been observed in myeloid leukemogenesis as Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. Yet the mechanism how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Here we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analyses identified increased Histone H3K27Ac signals at the super-enhancers such as Erg, Aff3, Spns2 and Coro2 loci, as well as increased mRNA expression of these genes. The modification of super-enhancer activities is mostly achieved by degradation of C/EBP by Trib1 and the MEK/ERK pathway only slightly contributes to the activities. Silencing of Erg abrogates the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of AML cells with the BRD4 inhibitor JQ1 showed growth inhibition in the Trib1/Erg-dependent manner. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential target of Hoxa9-associated AML.

2020-10-21 | GSE140313 | GEO

Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [array]

Project description:Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [array]

| PRJNA586761 | ENA

Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [ChIP-seq]

Project description:Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9 [ChIP-seq]

| PRJNA589286 | ENA

Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9.

Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPα and interacts with MEK1 to enhance extracellular signal-regulated kinase (ERK) phosphorylation. A close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis, where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. Chromatin immunoprecipitation sequencing analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased messenger RNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPα p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

| S-EPMC7976434 | biostudies-literature

Trib1 promotes acute myeloid leukemia progression by modulating transcriptional programs of Hoxa9

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-21 | GSE140315 | GEO

NUP98-HOXA9 acute myeloid leukemia

Project description:Mass Spectrometry analysis of the interactome of the oncoprotein NUP98-HOXA9

2017-07-10 | PXD001828 | Pride

Trib1 promotes the development of acute myeloid leukemia in the Ts1Cje Down syndrome model mouse

Project description:Down syndrome (DS) is caused by trisomy of chromosome 21 and it predisposes to hematological disorders such as transient myeloproliferative disorder and acute megakaryocytic leukemia. Our previous study identified a gain-of-function mutation of TRIB1 encoding a pseudokinase that suppresses C/EBP and enhances MEK/ERK signaling. In this study, we aimed to examine whether Trib1 expression cooperates with trisomy 21 in the development of leukemia. The wild type or R107L mutant Trib1 was retrovirally introduced into bone marrow cells derived from the Ts1Cje Down syndrome model mice or C57Bl6/J mice. Trib1 expression in hematopoietic cells of Ts1Cje mice accelerated the onset of AML development compared with that in wild type mice. Gene expression analysis showed up-regulation of Hox downstream genes and down-regulation of genes for the myeloid differentiation program and C/EBP targets. These results suggest that Trib1-mediated signaling plays an important role in promoting leukemogenesis in Down syndrome. We used microarrays to detail the global program of gene expression in mouse AML

2022-03-29 | GSE168531 | GEO

TRIB1 suppression on human hepatocytes transcriptome

2015-04-13 | GSE61473 | GEO

TRIB1 suppression on human hepatocytes transcriptome

Project description:The TRIB1 locus has been associated with lipid dysfunction. The underlying mechanisms were investigated by examining the transcription landscape in response to TRIB1 suppression in human primary hepatocytes. Primary hepatocytes from 3 distinct donors were exposed for 48 h to an antisense nucleotide targeting TRIB1 or a control nucleotide. The resulting impacts on the transcription profile were assessed using Human Transcriptome 2.0 microarrays (Affymetrix).

2015-04-13 | E-GEOD-61473 | biostudies-arrayexpress

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