Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation.
Physiologic Expression of Sf3b1(K700E) Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation.
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DOI：
10.1016/j.ccell.2016.08.006
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发表时间：
2016-09-12
期刊：
影响因子：
50.3
通讯作者：
Ebert BL
中科院分区：
文献类型：
--
作者：
Obeng EA;Chappell RJ;Seiler M;Chen MC;Campagna DR;Schmidt PJ;Schneider RK;Lord AM;Wang L;Gambe RG;McConkey ME;Ali AM;Raza A;Yu L;Buonamici S;Smith PG;Mullally A;Wu CJ;Fleming MD;Ebert BL
在骨髓增生异常综合征(MDS)的环状铁粒母细胞亚型难治性贫血患者中，超过80%的患者存在剪接因子3B亚单位1(SF3B1)突变。我们建立了最常见的SF3B1突变Sf3b1K700E的条件性敲入小鼠模型。Sf3b1K700E小鼠由于终末期红系成熟缺陷、红系发育不良和长期的造血干细胞(LT-HSC)扩增而患上大细胞性贫血。Sf3b1K700E髓系祖细胞和SF3B1突变的MDS患者样本显示出异常的3‘剪接位点选择与增加的无意义介导的衰退相关。TET2缺失与Sf3b1K700E协同导致更严重的红系和LT-HSC表型。此外，剪接体调节剂E7017选择性地杀死表达SF3B1K700E的细胞。因此，SF3B1K700E的表达反映了MDS突变的表型，可能成为MDS的治疗靶点。Obeng等人。产生带有SF3B1K700E的敲门小鼠，SF3B1K700E是骨髓增生异常综合征(MDS)的一种常见突变。SF3B1+/K700E小鼠表现出MDS特征。表达SF3B1K700E的小鼠和人MDS细胞表现出异常的3‘剪接位点选择，SF3B1K700E使细胞对剪接体调节剂敏感。
Over 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knock-in mouse model of the most common SF3B1 mutation, Sf3b1K700E. Sf3b1K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3’ splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1K700E-expressing cells. Thus, SF3B1K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS. Obeng et al. generate knockin mice with SF3B1K700E, a prevalent mutation in myelodysplastic syndrome (MDS). Sf3b1+/K700E mice display characteristics of MDS. Mouse and human MDS cells expressing SF3B1K700E exhibit aberrant 3’ splice site selection, and SF3B1K700E sensitizes cells to a spliceosome modulator.
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影响因子：
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