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Series GSE71475 Query DataSets for GSE71475
Status Public on Jun 23, 2016
Title Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene expression program and acute leukemia development
Organism Mus musculus
Experiment type Expression profiling by array
Genome binding/occupancy profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Summary 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
Citation(s) 27344947
Submission date Jul 29, 2015
Last update date Mar 19, 2019
Contact name Rui Lu
Organization name UNC at Chaple Hill
Street address 450 West Drive, CB 7295
City Chapel Hill
State/province NC
ZIP/Postal code 27599-7295
Country USA
Platforms (3)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
GPL13112 Illumina HiSeq 2000 (Mus musculus)
GPL17400 [MoGene-2_1-st] Affymetrix Mouse Gene 2.1 ST Array [transcript (gene) version]
Samples (45)
GSM1834191 EV_RAS_day12_1
GSM1834192 EV_RAS_day12_2
GSM1834193 RH_RAS_day12_1
This SuperSeries is composed of the following SubSeries:
GSE71437 Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray)
GSE71439 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)
GSE71472 Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq)
BioProject PRJNA291347

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE71475_RAW.tar 5.3 Gb (http)(custom) TAR (of BEDGRAPH, BIGBED, CEL)

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