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 (TGF) 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 TGF 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 TGF signaling and alternative splicing while hindering HSC fitness. SOURCE: H. Leighton Grimes (Lee.Grimes@cchmc.org) - Grimes Cincinnati Childrens Hospital Medical Center

Pluto Bioinformatics

GSE115903: Understanding Early Stage Myelodysplastic Syndrome Pathobiology