|
| Status |
Public on Nov 28, 2018 |
| Title |
Understanding Early Stage Myelodysplastic Syndrome Pathobiology |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Delineating key HSC regulators is of significant interest for informing the treatment of hematologic malignancy. While HSC activity is enhanced by overexpression of SKI, the transforming growth factor-beta (TGFβ) signaling antagonist corepressor, its requirement in HSC is unknown. Here we reveal a profound defect in Ski-/- HSC fitness but not specification. Transcriptionally, Ski-/- HSC exhibited striking upregulation of TGFb superfamily signaling and splicing alterations. As these are both common aspects of myelodysplastic-syndrome (MDS) pathobiology with prognostic value, we investigated the role of SKI in MDS. A SKI-correlated gene signature defines a subset of low-risk MDS patients with active TGFβ signaling and deregulated RNA splicing (e.g. CSF3R). The apparent paradox of Ski-/- HSC sharing molecular aspects of MDS with elevated SKI-mRNA is resolved by miR-21 targeting of SKI in MDS. We conclude that miR-21-mediated loss of SKI contributes to early stage MDS pathogenesis by activating TGFβ signaling and alternative splicing while hindering HSC fitness.
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| |
|
| Overall design |
Single cell RNA seq of transplanted fetal liver-derived hematopoietic stem cells
|
| |
|
| Contributor(s) |
Muench DE, Salomonis N, Grimes HL |
| Citation(s) |
30249787 |
| Submission date |
Jun 17, 2018 |
| Last update date |
Mar 21, 2019 |
| Contact name |
H. Leighton Grimes |
| E-mail(s) |
Lee.Grimes@cchmc.org
|
| Phone |
513-636-6089
|
| Organization name |
Cincinnati Childrens Hospital Medical Center
|
| Department |
Immunobiology
|
| Lab |
Grimes
|
| Street address |
3333 Burnet Ave. MLC 7038
|
| City |
Cincinnati |
| State/province |
OH |
| ZIP/Postal code |
45229 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
|
| Samples (94)
|
|
| Relations |
| BioProject |
PRJNA476461 |
| SRA |
SRP150686 |
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