AI Article Synopsis
- - SF3B1 splicing factor mutations are commonly found in myelodysplastic syndromes (MDS) with ring sideroblasts, leading to abnormal red blood cells filled with iron; however, the mechanism behind this is not well understood.
- - Researchers developed an induced pluripotent stem cell model that successfully mimicked the formation of ring sideroblasts during the differentiation of red blood cells, revealing that mutant SF3B1 causes missplicing of around 100 genes.
- - Key mitochondrial transporters TMEM14C and ABCB7 are misspliced due to SF3B1 mutations, leading to reduced protein levels and increased iron accumulation in mitochondria, ultimately resulting in the formation of ring sideroblast
Article Abstract
SF3B1 splicing factor mutations are near-universally found in myelodysplastic syndromes (MDS) with ring sideroblasts (RS), a clonal hematopoietic disorder characterized by abnormal erythroid cells with iron-loaded mitochondria. Despite this remarkably strong genotype-to-phenotype correlation, the mechanism by which mutant SF3B1 dysregulates iron metabolism to cause RS remains unclear due to an absence of physiological models of RS formation. Here, we report an induced pluripotent stem cell model of SF3B1-mutant MDS that for the first time recapitulates robust RS formation during in vitro erythroid differentiation. Mutant SF3B1 induces missplicing of ∼100 genes throughout erythroid differentiation, including proposed RS driver genes TMEM14C, PPOX, and ABCB7. All 3 missplicing events reduce protein expression, notably occurring via 5' UTR alteration, and reduced translation efficiency for TMEM14C. Functional rescue of TMEM14C and ABCB7, but not the non-rate-limiting enzyme PPOX, markedly decreased RS, and their combined rescue nearly abolished RS formation. Our study demonstrates that coordinated missplicing of mitochondrial transporters TMEM14C and ABCB7 by mutant SF3B1 sequesters iron in mitochondria, causing RS formation.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972092 | PMC |
| http://dx.doi.org/10.1182/blood.2021012652 | DOI Listing |
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