Vitamin B6 addiction in acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA587508 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10399002.fastq.gz | Fastqsanger.gz | |||
| SRR10399003.fastq.gz | Fastqsanger.gz | |||
| SRR10399004.fastq.gz | Fastqsanger.gz | |||
| SRR10399005.fastq.gz | Fastqsanger.gz | |||
| SRR10399006.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cells rely on altered metabolism to support abnormal proliferation. We performed a CRISPR/Cas9 functional genomic screen targeting metabolic enzymes and identified PDXK-an enzyme that produces pyridoxal phosphate (PLP) from vitamin B6-as an acute myeloid leukemia (AML)-selective dependency. PDXK kinase activity is required for PLP production and AML cell proliferation, and pharmacological blockade of the vitamin B6 pathway at both PDXK and PLP levels recapitulated PDXK disruption effects. PDXK disruption reduced intracellular concentrations of key metabolites needed for cell division. Furthermore, disruption of PLP-dependent enzymes ODC1 or GOT2 selectively inhibited AML cell proliferation and their downstream products partially rescued PDXK disruption induced proliferation blockage. Our work identifies the vitamin B6 pathway as a pharmacologically actionable dependency in AML.
| S-EPMC7197326 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-01-13 | GSE139908 | GEO
Project description:The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukemia (AML) genomes. Ascorbic Acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukemic model expressing IDH1R132H. Vitamin C treatment induced an IDH1R132H dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation. Vitamin C induced differentially methylated regions (DMRs) that displayed a significant overlap with enhancers implicated in myeloid differentiation and were enriched in sequence elements for the hematopoietic transcription factors RUNX1 and PU.1. ChIP-seq of PU.1 and RUNX1 revealed a significant loss of PU.1 and increase of RUNX1 bound DNA elements accompanied by their demethylation following vitamin C treatment. Additionally, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. Based on these data we propose a model of vitamin C induced epigenetic remodelling of transcription factor binding sites driving differentiation in a leukemic model.
2017-07-01 | GSE87623 | GEO
Project description:Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses in vitro and in vivo. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5’-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.
2021-08-31 | GSE182999 | GEO
Project description:Due to the current opioid epidemic, a better understanding of genetic and environmental factors that contribute to opioid addiction is warranted. To explore the potential causative role of VitD in opioid addiction , we used multiple pharmacologic approaches and genetic mouse models. We used profiled the transcriptome of key brain reward regions upon morphine treatment in vitamin D receptor KO and wild type mice. Our results highlight the role of VitD deficiency in the development of addiction and suggest a potential therapeutic benefit of VitD supplementation for VitD deficient individuals in the prevention and management of addiction.
2021-04-25 | GSE171683 | GEO
Project description:The epigenetic treatment by 3-Deazaneplanocin A (DZNep), a histone methyltransferase inhibitor, shows great potential against acute myeloid leukemia (AML). However, the variant sensitivity and incomplete response to DZNep are commonly observed. We reveal that vitamin C (Vc) dramatically promotes DZNep response against leukemic cells in different cell lines and primary AML samples. To examine the molecular determinants underlying Vc enhanced anti-leukemia effect of DZNep, we conducted a genome-wide RNA sequencing and a gene ontology (GO) enrichment analysis of differentially expressed mRNAs in each group was performed.
2022-09-30 | GSE192629 | GEO
Project description:Vitamin B6 comprises six vitamers, pyridoxal, pyridoxine, pyridoxamine, pyridoxal 5′-phosphate (PLP), pyridoxine 5′-phosphate (PNP), and pyridoxamine 5′-phosphate (PMP), recognized for pleiotropic functions in mitigating oxidative stress and modulating metabolic homeostasis. This study reveals that PMP exhibits broad-spectrum antibacterial activity against pathogens, including Aeromonas hydrophila (A. hydrophila), Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella. In vitro assays demonstrated that high-dose PMP disrupts bacterial membrane integrity, triggering extensive extracellular DNA leakage and bactericidal effects. Furthermore, we identified Pediococcus acidilactici GR-6 and Lactobacillus fermentum GR-7, isolated from crucian carp gut, that synergistically synthesize vitamin B6 de novo during pathogens co-culture, achieving ≥63% inhibition of polymicrobial pathogens. Integrated genomic, proteomic and metabolomic analyses confirm that GR-6/GR-7 consortium regulates pyridoxal kinase and pyridoxine 4-dehydrogenase, maintaining vitamin B6 primarily as pyridoxine (84%) and PMP (16%). In A. hydrophila-infected crucian carp, dietary supplementation with GR-6/GR-7 consortium increases survival by 50%, with restored gut microbiota diversity and attenuated systemic inflammation (Alkaline phosphatase, Lysozyme and GSH/GSSG ratio). Metabolomics showed that probiotics-mediated elevation of intestinal content PMP level directly inhibits A. hydrophila infection. Collectively, this study establishes PMP as a novel probiotic metabolite that directly eliminates pathogens and resolving gut microbiome-host metabolic dysregulation.
2026-01-26 | PXD070947 | Pride
Project description:Hippocampal apoptosis is a characteristic feature of penumococcal meningitis associated with learning and memory deficitis as a sequel of the disease. We investigated the effect of vitamin B6 using an established infant rat model of experimental pneumococcal meningitis by histomorphology, transcriptomics and measurement of cellular nicotine amide adenine dinucleotide content. The data provides evidence that vitamin B6 is neuroprotecitve in terms of reduced hippocampal apoptosis involving reduction of the inflammatory response, preservation of cellular energy stores and up-regulated brain-derived neurotrophic factor levels.
2012-02-20 | E-MEXP-3555 | biostudies-arrayexpress
Project description:Vitamin C promotes anti-leukemia of DZNep in Acute Myeloid Leukemia
| PRJNA792424 | ENA
Project description:Background: Although the bile acid-mediated microbiome-host interaction is known to shape both the composition and functionality of the gut microbiome, the mechanisms by which bile acid stress influences specific microbial metabolic interactions remain poorly understood. To address this gap, we examine the metabolic interplay between two key gut microbes. Bacteroides thetaiotaomicron, one of the most abundant species, possesses a broad enzymatic repertoire for polysaccharide degradation, while Collinsella aerofaciens is associated with liver-related diseases and plays a role in modifying primary bile acids. Results: In anaerobic coculture, C. aerofaciens mitigated the inhibitory effects of deoxycholic acid (DCA) on B. thetaiotaomicron by absorbing DCA from the medium and partially converting it into glycine-conjugated derivatives. Proteomic analysis showed that DCA broadly disrupted amino acid and vitamin metabolism pathways, particularly in B. thetaiotaomicron. In contrast, coculture led to a general upregulation of these pathways in C. aerofaciens, with a marked activation of vitamin B6 metabolism. Additionally, C. aerofaciens exhibited increased production of citrulline and ornithine in coculture. Conclusions: C. aerofaciens alleviates DCA toxicity on B. thetaiotaomicron through absorption, while promoting amino acid and vitamin metabolism, including the vitamin B6 synthesis pathway, during coculture. These results suggest that microbial interactions can enhance resistance to bile acid stress and may influence gut microbiome resilience, with potential relevance for liver- and bile acid–related disorders.
2026-01-06 | PXD069395 | Pride