SKI controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness

David E. Muench, Kyle Ferchen, Chinavenmeni S. Velu, Kith Pradhan, Kashish Chetal, Xiaoting Chen, Matthew T. Weirauch, Clemencia Colmenares, Amit Verma, Nathan Salomonis, H. Leighton Grimes

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 deregulated expression of spliceosome genes (including Hnrnpk). Moreover, novel single-cell splicing analyses demonstrated that Ski-/- HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21-mediated loss of SKI activates TGF-β signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDSgenic clones.

Original languageEnglish (US)
Pages (from-to)E24-E34
JournalBlood
Volume132
Issue number21
DOIs
StatePublished - Nov 22 2018

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., & Grimes, H. L. (2018). SKI controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness. Blood, 132(21), E24-E34. https://doi.org/10.1182/blood-2018-06-860890