期刊
BLOOD
卷 132, 期 21, 页码 E24-E34出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-06-860890
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资金
- National Institutes of Health, National Institute of Environmental Health Sciences [T32 ES007250]
- National Heart, Lung, and Blood Institute [HL122661]
- National Cancer Institute [CA196658]
- Edward P. Evans Foundation
The transforming growth factor beta (TGF-beta) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-beta signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-beta signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-beta signaling. We found that a TGF-beta 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-beta antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-beta 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-beta 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-beta signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDSgenic clones.
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