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DOT1L inhibitors block abnormal self-renewal induced by cohesin loss [ChIP-seq]

UID: 10646

Author(s): Heimbruch, Katelyn E., Rao, Sridhar

Publisher(s): Medical College of Wisconsin

Description
Summary from GEO: "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 from GEO: "ChIP-sequencing of 4 conditions, 3 replicates per condition."
Subject of Study
Mus musculus
Subject(s)
Cell Cycle Proteins
Homeodomain Proteins
Leukemia, Myeloid, Acute
Loss of Function Mutation
OncoTree Cancer Type(s)
Acute Myeloid Leukemia
Access via GEO

TAR of BigWig files of genome binding/occupancy profiling by high throughput sequencing
Accession #: GSE140360

Access via SRA

ChIP sequencing of 14 samples
Accession #: SRP229754

Access via BioProject

Additional information about overall initiative.
Accession #: PRJNA589335

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications
Heimbruch K, Fisher J, Stelloh C, et al. DOT1L inhibitors block abnormal self-renewal induced by cohesin loss. Scientific Reports. 2021; 11:7288.
Data Type
Genomic
Equipment Used
Illumina NextSeq 500
Software Used
SRA Toolkit

The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.

Dataset Format(s)
SRA, TAR, BIGWIG
Dataset Size
3.5 GB (TAR of BIGWIG), 21.5 Gb (SRA)
Data Catalog Record Updated
2023-12-07