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Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia

ABSTRACT: Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia

PROVIDER: PRJNA673401 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12952858_1.fastq.gz	Fastqsanger.gz
	SRR12952858_2.fastq.gz	Fastqsanger.gz
	SRR12952859_1.fastq.gz	Fastqsanger.gz
	SRR12952859_2.fastq.gz	Fastqsanger.gz
	SRR12952860_1.fastq.gz	Fastqsanger.gz

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Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia

Project description:We evaluated differentially expressed genes in Nrf2-High/Low group and found that high Nrf2 expression significantly inhibited the DNA MMR pathway in AML.

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Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia by inhibiting MSH2.

Project description:Nuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) plays an important role in cancer chemoresistance. However, little is known about the role of Nrf2 in tumor mutation burden and the effect of Nrf2 in modulating DNA mismatch repair (MMR) gene in acute myeloid leukemia (AML). Here we show that Nrf2 expression is associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had a higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of drug resistance associated with a gene mutation in vivo. Furthermore, Nrf2 overexpression inhibited MutS Homolog 2 (MSH2) protein expression, which caused DNA MMR deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells inhibited the expression of the MSH2 protein. Our findings provide evidence that high Nrf2 expression can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.

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Nrf2 bindng in C2C12 myotubes

Project description:Nrf2 (NF-E2-related-factor-2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic Î²-cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1-knockout (Keap1MuKO) mice that express abundant Nrf2 in SkM and then examined Nrf2-target gene expression in this tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated, and the levels of glycogen branching enzyme (Gbe1) mRNA, along with those of glycogen branching enzyme (GBE) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2-inducers promoted Gbe1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin-immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced, and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2-induction in SkM increases GBE expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Chromatin occupancy of Nrf2 under CDDO-Im-treated condition were generated by deep sequencing, in dupliplicate

2016-04-06 | E-GEOD-78780 | biostudies-arrayexpress

Adolescent circadian rhythm disruption increases reward and risk-taking

Project description:Adolescent circadian rhythm disruption increases reward and risk-taking

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Transcription profiling of wild type and Nrf2 knock out treated with 100% oxygen to induce lung injury mice to provide insight to the downstream effector genes regulated by Nrf2

Project description:Nrf2 is a transcription factor that binds to antioxidant response elements of the regulatory region of a number of antioxidant genes. A mutation in the Nrf2 gene increases susceptibility to hyperoxic lung injury. This project examines expression differences between wild type and Nrf2 knock out mice with the hope of providing insight to the downstream effector genes regulated by Nrf2.

2007-12-14 | E-GEOD-495 | biostudies-arrayexpress

Nrf2 transcript alterations

Project description:WGS and RNA-seq data for Nrf2 study

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Expression data from Keap1 overexpression and Nrf2 knockdown lung cancer cell

Project description:Keap1 overexpressed and Nrf2 depleted CL1-5 cells were used to identify genes regulated by Keap1/Nrf2 axis-dependent gene regulations We used microarrays to detail the global programme of gene expression underlying metastasis and identified distinct classes of Keap1/Nrf2-regulated genes during this process. CL1-5 cells stably expressed Keap1 expressing construct and Nrf2-specific shRNA were analyzed compared to control cells

2015-03-04 | E-GEOD-66473 | biostudies-arrayexpress

Comparison of genetic and pharmacologic activation of Nrf2 signaling

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Transcription profiling of mouse Keap1-null (CKO) to investigate genetic and pharmacologic activation of Nrf2 signaling

Project description:Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct hepatic gene expression profiles between Keap1 knockout and triterpenoid treated mice; Loss of Nrf2 signaling increases susceptibility to acute toxicity, inflammation, and carcinogenesis in mice due to the inability to mount adaptive responses. By contrast, disruption of Keap1 (a cytoplasmic modifier of Nrf2 turnover) protects against these stresses in mice; although dominant negative mutations in Keap1 have been identified recently in some human cancers. Global characterization of Nrf2 activation is important to exploit this pathway for chemoprevention in healthy, yet at-risk individuals and also to elucidate the consequences of hijacking the pathway in Keap1-mutant human cancers. This analysis also enables a global characterization of the pharmacodynamic action of CDDO-Im at a low dose that is relevant to chemoprevention. Experiment Overall Design: Liver-targeted conditional Keap1-null (CKO) mice provide a model of genetic activation of Nrf2 signaling. By coupling global gene expression analysis of CKO mice with analysis of pharmacologic activation using the synthetic oleanane triterpenoid CDDO-Im, we are able to gain insight into pathways affected by Nrf2 activation. CDDO-Im is an extremely potent activator of Nrf2 signaling. CKO mice were used to identify genes modulated by genetic activation of Nrf2 signaling. The CKO response was compared to hepatic global gene expression changes in wild-type mice treated with CDDO-Im at a maximal Nrf2 activating dose. n=3/group, male 9 week old mice were used. Mice were treated with a single dose of vehicle (10% Cremophor-EL, 10% DMSO, and PBS) or 30 umol CDDO-Im/kg body weight by gavage and sacrificed 6 h later.

2009-05-11 | E-GEOD-15633 | biostudies-arrayexpress

Project description:Obesity-related T cell dysfunction impairs immunosurveilance and increases cancer risk

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