Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes.
Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes.
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剪接因子SF 3B 1是骨髓增生异常综合征（MDS）中最常见的突变基因，与环形铁粒幼细胞（RS）的存在密切相关。我们对SF 3B 1突变型MDS伴RS患者的造血干细胞（HSC）RNA测序数据进行了系统分析。在许多下游靶基因中发现了异常剪接事件，并且在SF 3B 1突变型MDS中，隐蔽的3′剪接位点使用是常见的事件。铁转运蛋白ABCB 7是一个公认的候选基因，在MDS伴RS中表现出显著的下调。我们的分析揭示了异常ABCB 7剪接，由于MDS患者样本中使用了一个选择性3′剪接位点，导致ABCB 7 mRNA中出现提前终止密码子。用无义介导的衰变（NMD）抑制剂放线菌酮处理培养的SF 3B 1突变型MDS成红细胞和CRISPR/Cas9产生的SF 3B 1突变型细胞系表明，异常剪接的ABCB 7转录物是NMD的靶向。我们描述了SF 3B 1突变型MDS的HSC中的隐蔽剪接事件，我们的数据支持了一个模型，在该模型中，由突变型SF 3B 1引起的异常剪接导致的NMDA诱导的铁输出蛋白ABCB 7 mRNA转录的下调是MDS患者RS中线粒体铁积累增加的基础。
The splicing factor SF3B1 is the most frequently mutated gene in myelodysplastic syndromes (MDS), and is strongly associated with the presence of ring sideroblasts (RS). We have performed a systematic analysis of cryptic splicing abnormalities from RNA sequencing data on hematopoietic stem cells (HSCs) of SF3B1-mutant MDS cases with RS. Aberrant splicing events in many downstream target genes were identified and cryptic 3′ splice site usage was a frequent event in SF3B1-mutant MDS. The iron transporter ABCB7 is a well-recognized candidate gene showing marked downregulation in MDS with RS. Our analysis unveiled aberrant ABCB7 splicing, due to usage of an alternative 3′ splice site in MDS patient samples, giving rise to a premature termination codon in the ABCB7 mRNA. Treatment of cultured SF3B1-mutant MDS erythroblasts and a CRISPR/Cas9-generated SF3B1-mutant cell line with the nonsense-mediated decay (NMD) inhibitor cycloheximide showed that the aberrantly spliced ABCB7 transcript is targeted by NMD. We describe cryptic splicing events in the HSCs of SF3B1-mutant MDS, and our data support a model in which NMD-induced downregulation of the iron exporter ABCB7 mRNA transcript resulting from aberrant splicing caused by mutant SF3B1 underlies the increased mitochondrial iron accumulation found in MDS patients with RS.
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