SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness

The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal–correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-β antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-β signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski–/– HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski–/– HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski–/– hematopoiesis in the absence of transplantation. Similar to SKI-high MDS patient samples, Ski–/– HSCs strikingly upregulated TGF-β signaling and deregulat...
Source: Blood - Category: Hematology Authors: Tags: Myeloid Neoplasia, e-Blood Source Type: research