Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

ABSTRACT: Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

PROVIDER: PRJNA937683 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

Project description:DNA methyltransferases DNMT3A- and DNMT3B-mediated de novo DNA methylation critically regulates epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote macro-oligomer formation, leading to aberrant DNA methylation that in turn contributes to pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the hotspot mutation-induced functional mis-regulation of DNMT3A remains unclear. Here, we report the crystal structure of DNMT3A methyltransferase (MTase) domain, revealing a molecular basis for its DNMT3B-distinct oligomerization behavior. Introducing DNMT3B-converting mutations to DNMT3A R882 mutants also led to structure determination of R882H- and R882C-mutated DNMT3A, which show enhanced intermolecular contacts than wild-type DNMT3A. Consistently, our in vitro and genomic DNA methylation analyses reveal that the DNMT3B-converting mutations eliminate the gain-of-function effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutation-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

2023-12-31 | GSE225828 | GEO

Structure-guided functional suppression of AML-associated DNMT3A R882 mutations [methylation]

2023-12-31 | GSE226062 | GEO

Structure-guided functional suppression of AML-associated DNMT3A R882 mutations [methylation]

Project description:Structure-guided functional suppression of AML-associated DNMT3A R882 mutations [methylation]

| PRJNA938470 | ENA

Targeting of DNMT3A hotspot mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia

Project description:Somatic mutations in DNA Methyltransferase 3A (DNMT3A) with a hotspot in exon 23 at Arginine 882 (DNMT3AR882mut) are the most frequent single mutations in clonal hematopoiesis. Here we analyze the expression of genes and endogenous retrovirus (ERV) sequences in a murine model carrying human DNMT3A-R882H mutation in one allele of the endogenous DNMT3A with respect to normal condition and azacitidine treatment.

2021-01-26 | GSE146907 | GEO

Hotspot DNMT3A and IDH1/2 Mutations in Acute Myeloid Leukemia and Their Relevance as Targets for Immunotherapy

Project description:DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1 & 2 (IDH1/2) are genes involved in epigenetic regulation, each mutated in 7-23% of acute myeloid leukemia (AML). Here, we investigated whether hotspot mutations in these genes encode neoantigens that can be targeted by immunotherapy. Five EBV-B cell lines expressing common HLA class I alleles were transduced with a minigene construct containing mutations that often occur in DNMT3A or IDH1/2. Peptides eluted from HLA class I alleles on these EBV-B cell lines were analyzed by tandem mass spec-trometry. We identified an HLA-A*01:01-binding DNMT3AR882H peptide and HLA-B*07:02-binding IDH2R140Q peptide, for which we searched for specific T cells in healthy individuals using pep-tide-HLA tetramers. Various T-cell clones were isolated showing specific reactivity against cell lines transduced with full-length DNMT3AR882H or IDH2R140Q genes, while cell lines transduced with wildtype genes were not recognized. One T-cell clone for DNMT3AR882H also reacted against patient AML cells with the mutation, while AML cells without the mutation were not recognized, thereby validating surface presentation of a DNMT3AR882H neoantigen that can potentially be targeted on HLA-A*01:01 positive AML by immunotherapy.

2024-06-23 | PXD050560 | Pride

Targeting of DNMT3A hotspot mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia

Project description:Targeting of DNMT3A hotspot mutations in Clonal Hematopoiesis and Acute Myeloid Leukemia

| PRJNA612341 | ENA

Evidence supporting a dominant negative mechanism for DNMT3A hotspot mutation-mediated leukemic cell transformation

Project description:Evidence supporting a dominant negative mechanism for DNMT3A hotspot mutation-mediated leukemic cell transformation

| PRJNA533827 | ENA

Transcription profiling of acute monocytic leukemia (AML-M5) patients with DNMT3A mutations

Project description:To understand the pathogenesis of DNMT3A in acute monocytic leukemia (AML-M5), we identified genes that are expressed differently in leukemia cells from AML-M5 patients collected at diagnosis with DNMT3A mutations (6 cases) compared to those without the mutations (4 cases). Differences of expression level were observed in 889 out of 20,723 (4.3%) annotated genes by using Affymetrix microarray with 469 genes upregulated and 420 genes downregulated. Leukemia cells in bone marrow of acute monocytic leukemia patients were collected at diagnosis for RNA extraction and hybridization on Affymetrix microarrays. 6 cases of AML-M5 samples with DNMT3A mutations and 4 cases of AML-M5 samples wihtout DNMT3A mutations were used.

2011-02-12 | E-GEOD-27187 | biostudies-arrayexpress

miR196b-/- DNMT3A-mutant AML [RNA-seq]

Project description:miR196b-/- DNMT3A-mutant AML [RNA-seq]

| PRJNA792547 | ENA

RNA sequencing of patient derived xenograft sample AML-346, AML-356, AML-388 and AML-661 using prime-seq

Project description:We generate CRISPR/Cas9 patient derived xenograft (PDX) models of acute myeloid leukemia. Mimicking anti-cancer therapy in patients, PDX cells with gene knockouts were re-transplanted into mice. In fluorochromes guided, competitive in vivo trials, a subset of PDX models showed a clear growth disadvantage upon knockout, indicating essential functions for WT1 and DNMT3A.

2022-10-18 | GSE215836 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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