SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes
SF3B1 haploinsufficiency leads to formation of ring sideroblasts in myelodysplastic syndromes
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DOI：
10.1182/blood-2012-05-430876
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发表时间：
2012-10-18
期刊：
影响因子：
20.3
通讯作者：
Tiu, Ramon V.
中科院分区：
文献类型：
--
作者：
Visconte, Valeria;Rogers, Heesun J.;Tiu, Ramon V.
全外显子组/基因组测序是鉴定骨髓增生异常综合征（mds）和其他血液病剪接体机制体细胞突变的基础。SF3B1，剪接因子3b亚基1在60%-80%的难治性贫血伴环状铁母细胞（RARS）和伴血小板增多的RARS (RARS- t)， MDS和MDS/骨髓增生性肿瘤（MDS / mpn）的两种不同亚型中发生突变。RARS/RARS- t的一个特殊特征是线粒体中存在以铁超载为特征的异常铁母细胞，称为RS。基于RARS/RARS- t中SF3B1突变的高频率，我们研究了SF3B1改变的后果。超微结构上，SF3B1突变体与野生型RARS患者相比，铁分布发生改变，表现为粗铁沉积。在K562细胞中进行SF3B1基因敲除实验，通过RT-PCR结果显示，s2型内含子剪接下调。SF3B1突变体的rna测序分析显示，与md发病相关的基因使用差异，如ASXL1、CBL、EZH和RUNX家族。SF3B药物抑制剂米亚霉素在健康BM细胞中诱导RS的形成。此外，Sf3b1杂合敲除小鼠的骨髓抽吸液显示普鲁士蓝RS。总之，我们报告了SF3B1与RS表型之间关联的第一个实验证据。我们的数据表明SF3B1单倍不足导致RS的形成。(血。2012;120 (16):3173 - 3186)
Whole exome/genome sequencing has been fundamental in the identification of somatic mutations in the spliceosome machinery in myelodysplastic syndromes (MDSs) and other hematologic disorders. SF3B1, splicing factor 3b subunit 1 is mutated in 60%-80% of refractory anemia with ring sideroblasts (RARS) and RARS associated with thrombocytosis (RARS-T), 2 distinct subtypes of MDS and MDS/myeloproliferative neoplasms (MDSs/MPNs). An idiosyncratic feature of RARS/RARS-T is the presence of abnormal sideroblasts characterized by iron over-load in the mitochondria, called RS. Based on the high frequency of mutations of SF3B1 in RARS/RARS-T, we investigated the consequences of SF3B1 alterations. Ultrastructurally, SF3B1 mutants showed altered iron distribution characterized by coarse iron deposits compared with wild-type RARS patients by transmission electron microscopy. SF3B1 knockdown experiments in K562 cells resulted in down-regulation of U2-type intron-splicing by RT-PCR. RNA-sequencing analysis of SF3B1 mutants showed differentially used genes relevant inMDSpathogenesis, such as ASXL1, CBL, EZH, and RUNX families. A SF3B pharmacologic inhibitor, meayamycin, induced the formation of RS in healthy BM cells. Further, BM aspirates of Sf3b1 heterozygous knockout mice showed RS by Prussian blue. In conclusion, we report the first experimental evidence of the association between SF3B1 and RS phenotype. Our data suggest that SF3B1 haploinsufficiency leads to RS formation. (Blood. 2012;120(16):3173-3186)