Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MAT2A as key regulator and therapeutic target in MLL leukemogenesis

ABSTRACT: Epigenetic dysregulation plays a pivotal role in MLL pathogenesis, therefore serving as suitable therapeutic point of attack. SAM is the universal methyl donor in human cells and is synthesized by MAT2A. MAT2A is already known to be deregulated in different cancer types. Here, we used our human CRISPR/Cas9-MLLr leukemia model, faithfully mimicking MLL patients’ pathology with indefinite growth potential in in vitro culture, to evaluate the unknown role of MAT2A as therapeutic target. Comparable to publicly available patient data, we detected MAT2A to be significantly overexpressed in our CRISPR/Cas9-MLLr model compared to healthy controls. By using non-MLLr and MLLr cell lines and our model, we detected an MLLr specific enhanced response to PF-9366, a new MAT2A inhibitor, by alteration of proliferation, viability, differentiation, apoptosis and cell cycling. Moreover, the combinational treatment of PF-9366 with chemotherapy or targeted therapies against the SAM-dependent methyltransferases DOT1L and PRMT5, revealed even more pronounced effects. In summary, we uncovered MAT2A as a key regulator in MLL leukemogenesis and its inhibition led to significant anti-leukemic effects. Therefore, our study paves the avenue for clinical application of PF-9366 to improve the treatment of poor prognosis MLLr leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141839 | GEO | 2020/06/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Quantitative cellular proteome analysis of Fetal- and Adult-Derived MLL-Rearranged Leukemia

Project description:Infant and adult MLL-rearranged (MLLr) leukemia represents a disease with few treatment options and a dismal prognosis. Here, we present an in-depth proteomic characterization of in utero-initiated and adult-onset MLLr leukemia in a mouse model of MLL-ENL-mediated leukemogenesis. We characterize early proteomic events of MLL-ENL-mediated transformation in fetal and adult progenitors.

2024-04-02 | PXD042249 | Pride

MAT2A and methionine dependency are indispensible for H3K27M mutant gliomas.

Project description:Gliomas bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors. H3K27M mutant tumors display unique epigenomes with global loss of the chromatin repressive H3K27 trimethylation mark. Here, we generated a syngeneic H3K27M mouse model to study the dependence upon amino acid (AA) metabolism by performing an AA drop out screen. H3K27M mutant cells, but not histone wildtype cells, were highly dependent on the amino acid, methionine. Interrogating the methionine cycle dependency through an siRNA screen identified the enzyme Methionine Adenosyltransferase 2A (MAT2A), which catalyzes production of S-adenosylmethionine (SAM), a methyl donor. Sensitivity to MAT2A loss in H3K27M mutant cells was not mediated through the canonical mechanism of MTAP deletion; instead, H3K27M mutant cells have lower MAT2A protein levels, which is mediated by Adenosylmethionine Decarboxylase 1 (AMD1) production of decarboxylated SAM (dcSAM). MAT2A loss induces global depletion of H3K36me3, a potent chromatin mark of transcriptional elongation, as evaluated by quantitative chromatin immunoprecipitation with reference exogenous genome sequencing (ChIP-Rx-Seq) in multiple DIPG lines. Tandem H3K36me3 ChIP-Rx-seq and RNA-seq identified several oncogenic and developmental transcriptional programs associated with MAT2A loss. Moreover, inducible knockdown of MAT2A or methionine-restricted diets (MR) extended survival in both syngeneic and patient-derived xenograft models (PDXs) in vivo. Collectively, our results provide novel connections between AA metabolism and the epigenome in H3K27M gliomas, suggesting that MAT2A, a central regulator of methionine metabolism, presents exploitable therapeutic vulnerabilities in H3K27M gliomas.

2022-01-28 | GSE160006 | GEO

TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part1

Project description:Hepatic stellate cell (HSC) activation induced by transforming growth factor β (TGF-β1) plays a pivotal role in the fibrogenesis. The complex downstream mediators of TGF-β1 are largely unknown. Here, proteomics analysis and biological validation demonstrated that methionine adenosyltransferase 2A (MAT2A) was significantly upregulated in a CCl4-induced fibrosis mice model and a small molecule NPLC0393, known to block TGF-β1/Smad3 signaling, inhibited its upregulation. In HSC cells, TGF-β1 induced elevation of MAT2A and MAT2β expression as well as reduction of S-adenosylmethionine (SAM) content, which further promoted HSC activation. Functionally, in vivo and in vitro knockdown of MAT2A alleviated CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitated hepatic fibrosis and abolished therapeutic effect of NPLC0393. TGF-β1 induced p65 phosphorylation and NF-κB activation, thereby promoted the transcription of MAT2A and its protein expression. In addition, overexpression of p65 abrogated NPLC0393 mediated inhibition of HSC activation. This study identified a novel pathway TGF-β1/p65/MAT2A that was involved in the regulation of intracellular SAM contents and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis.

2019-11-12 | PXD011134 | Pride

TGF-β1/p65/MAT2A: a novel pathway involved in the regulation of intracellular SAM and liver fibrogenesis - Part2

2019-11-12 | PXD011135 | Pride

Genome-wide mapping of MAT2A-associsted regions in bovine blastocysts

Project description:Methionine adenosyltransferase (MAT), that catalyzes the synthesis of S-adenosylmethionine (SAM) from ATP and methionine, is involved in folate-mediated one-carbon metabolism (OCM) that is essential for preimplantation embryos in terms of both short-term periconceptional development and long-term phenotypic programming beyond the periconceptional period. SAM is the universal methyl donor for epigenetic methylation of DNA and histones. In the context of the long-term phenotypic programming by the modulation of OCM during periconceptional period, possible interactions between MAT2A and epigenetic status of specific genes during this period are of particular interest. MAT2A has been proposed to interact with many chromatin-related proteins and be recruited to their specific target genes to constitute gene-regulatory complexes. Thus, in the aim of addressing the possible interaction of MAT2A with specific genomic DNA regions in periconceptional period, we performed a ChIP-seq analysis using MAT2A antibody against bovine blastocysts.

2017-06-19 | GSE85836 | GEO

NUDT21 regulates intron detention of the SAM synthetase MAT2A RNA

Project description:NUDT21 encodes the CFIm25 protein, a component of the CFIm complex that regulates alternative polyadenylation (APA). Our data suggest that the CFIm complex also induces splicing of a detained intron in the the S-adenosylmethionine (SAM) synthetase MAT2A to control intracellular levels of SAM. To genetically separate these functions, we used poly(A) Click-seq (PAC-seq) to determine the changes in poly(A) site selection in two cell lines. The parental cell line is the colorectal cell line HCT116 and a derivative line that has the detained intron of MAT2A deleted in both alleles of MAT2A (116-DDI). We found few differences in alternative polyadenylation after CFIm25 depletion were similar supporting teh conclusion that CFIm's role in APA is mechanistically distinct from its role in regulation of MATA splicing.

2021-05-04 | GSE158591 | GEO

8-Cl-Ado and 8-NH2-Ado Synergize with Venetoclax to Target the Methionine-MAT2A-SAM Axis in Acute Myeloid Leukemia

Project description:Background: Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Methods: Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Results: Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. Conclusions: These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

2023-11-09 | GSE247025 | GEO

Only hematopoietic stem and progenitor cells from cord blood are susceptible to malignant transformation by MLL-AF4 translocations

Project description:MLL rearrangements (MLLr) play a crucial role in leukemogenesis. Dependent on age, major differences exist regarding disease frequency, main fusion partners and prognosis. In infants, up to 80% of acute lymphoid leukemia (ALL) bear t(4;11) resulting in a poor prognosis. In contrast, in adults only 10% of acute myeloid leukemia (AML) bear t(9;11) with an intermediate prognosis. The reasons for these differences are only poorly understood. Recently, we established an efficient human patient-specific CRISPR/Cas9-based MLLr model in hematopoietic stem and progenitor cells (HSPCs) derived from human cord blood (huCB) faithfully mimicking the underlying biology of the disease. Here, we transfer this model into an adult system using HSPCs from adult bone marrow (huBM) allowing us to investigate the impact of the cell of origin and fusion partner on disease development. RNA-Seq uncovered an absent downregulation of FFAR2 in t(4;11) huBM, an epigenetic tumor suppressor, potentially responsible for the inability of MLL-AF4 to immortalize adult cells under myeloid conditions.

2020-07-20 | GSE148714 | GEO

Quantitative secretome analysis of fetal and adult hematopoietic progenitors during leukemia initiation and its response to Fibulin and/or Fibronectin treatment.

Project description:We describe the proteomic composition of the secretome of fetal and adult hematopoietic progenitors during MLL-rearranged (MLLr) leukemia initiation as well as the pre-leukemic cells’ secretion response to the treatment with Fibulin (Fbln1) and/or Fibronectin (Fn1) using data-independent acquisition mass spectrometry analysis.

2024-04-02 | PXD049014 | Pride

CRISPR screen identifies NUDT21 as a regulator of intron detention of the SAM synthetase MAT2A RNA

Project description:The only S-adenosymethionine (SAM) synthetase expressed in most human cells, MAT2A, is regulated by intron detention. Using a GFP fusion reporter, we conducted a CRISPR screen to identify regulators of this alternative splicing event. The screen identified METTL16, a known regulator of this process, and NUDT21. NUDT21 encodes the CFIm25 protein a member of the CFIm complex involved in alternative polyadenylation. Validation and follow-up studies support the idea that CFIm25 and the larger CFIm complex plays an unanticipated role in splicing of the MAT2A detained intron.

2021-05-04 | GSE172217 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data