DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3A R882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A R882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3A R882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A R882H-induced DNA hypomethylation impairs Meis1 expression.
More...DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3A R882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A R882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3A R882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A R882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A R882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias.
This SuperSeries is composed of the SubSeries listed below.
Overall design: Refer to individual Series
Less...| Accession | PRJNA291347; GEO: GSE71475 |
| Type | Umbrella project |
| Publications | Lu R et al., "Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development.", Cancer Cell, 2016 Jul 11;30(1):92-107 |
| Submission | Registration date: 29-Jul-2015
Univ of Alabama at Birmingham |
| Relevance | Superseries |
Project Data:
| Resource Name | Number
of Links |
|---|
| Sequence data |
| SRA Experiments | 24 |
| Publications |
| PubMed | 1 |
| PMC | 1 |
| Other datasets |
| BioSample | 24 |
| GEO DataSets | 6 |
GEO Data Details| Parameter | Value |
|---|
| Data volume, Spots | 947150 |
| Data volume, Processed Mbytes | 20 |
| Data volume, Supplementary Mbytes | 5696 |
| Parameter | Value |
|---|
| Data volume, Gbases | 105 |
| Data volume, Mbytes | 54009 |
Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene expression program and acute leukemia development encompasses the following 5 sub-projects:
| Project Type | Number of Projects |
| Epigenomics | 3 |
BioProject
accession | Organism | Title |
|---|
| PRJNA291345 | Mus musculus | Epigenomic profiling studies of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D (ChIP-seq) (Univ of Alabama at Birmingham) | | PRJNA291346 | Mus musculus | Effect of DNMT3A R882H mutation or WT expression on global DNA methylation patterns of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (eRRBS) (Univ of Alabama at Birmingham) | | PRJNA291344 | Mus musculus | Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq) (Univ of Alabama at Birmingham) |
|
| Transcriptome or Gene expression | 2 |
BioProject
accession | Organism | Title |
|---|
| PRJNA291209 | Mus musculus | Expression profiling of murine leukemia stem cell (LSC) lines established ex vivo by coexpression of R882H-mutated DNMT3A and NRAS-G12D post treatment with Dot1l inhibitor (Microarray) (UNC at Chaple Hill) | | PRJNA291210 | Mus musculus | Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray) (UNC at Chaple Hill) |
|