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| 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.
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| |
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| Overall design |
RNA-sequencing and ChIP-sequencing of 4 conditions, with 2-3 replicates per condition.
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| |
|
| 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)
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| This SubSeries is part of SuperSeries: |
| GSE140361 |
DOT1L inhibitors block abnormal self-renewal induced by cohesin loss |
|
| Relations |
| BioProject |
PRJNA589334 |
| SRA |
SRP229755 |
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