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Series GSE140359 Query DataSets for GSE140359
Status Public on Feb 25, 2021
Title DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [RNA-seq]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Acute myelogenous leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the mechanism underpinning the enhanced self-renewal conferred by cohesin haploinsufficiency. Using primary (HSPCs) as a model we demonstrate that a reduction in a core cohesin subunit is associated with decreased H3K27me3 and increased H3K79me2, along with increased self-renewal capacity and a leukemic transcriptional profile. Inhibition of DOT1L in cohesin-depleted HSPCs restored normal self-renewal, H3K27me3 and H3K79me2 levels, and gene expression, identifying DOT1L as a potential therapeutic target in cohesin haploinsufficient AML. Together our data further characterizes the mechanism by which cohesin mutations contribute to AML and identifies DOT1L as a potential therapeutic target for AML patients harboring cohesin mutations.
Overall design RNA-sequencing and ChIP-sequencing of 4 conditions, with 2-3 replicates per condition.
Contributor(s) Heimbruch KH, Rao S
Citation(s) 33790356
Submission date Nov 13, 2019
Last update date Apr 13, 2021
Contact name Katelyn Elizabeth Heimbruch
Organization name Medical College of Wisconsin
Street address 8727 Watertown Plank Road
City Miwaukee
State/province Wisconsin
ZIP/Postal code 53213
Country USA
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (11)
GSM4159957 WT-DMSO_RNA3_1repeat
This SubSeries is part of SuperSeries:
GSE140361 DOT1L inhibitors block abnormal self-renewal induced by cohesin loss
BioProject PRJNA589334
SRA SRP229755

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
GSE140359_RAW.tar 50.9 Mb (http)(custom) TAR (of GTF)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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