Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators.
Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators.
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DOI：
10.1261/rna.056101.116
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Heuser M
中科院分区：
文献类型：
--
作者：
Qiu J;Zhou B;Thol F;Zhou Y;Chen L;Shao C;DeBoever C;Hou J;Li H;Chaturvedi A;Ganser A;Bejar R;Zhang DE;Fu XD;Heuser M
骨髓增生异常综合征（MDS）是一种异质性骨髓疾病，在几个剪接因子中普遍存在突变，但与特定突变或MDS相关的剪接程序一般仍有待系统定义。我们应用RASL-seq，一种灵敏且具有成本效益的平台，在来自MDS患者或健康个体的169个样本中询问5502个注释的剪接事件。我们发现与正常造血谱系相关的剪接签名在很大程度上与细胞信号传导和分化程序相关，而MDS相关的签名主要参与细胞周期控制和DNA损伤反应。尽管受影响的剪接因子在3′剪接位点定义中具有共同的作用，但U2 AF 1、SRSF 2和SF 3B 1中的突变会影响不同的剪接程序，有趣的是，受影响的基因会进入会聚的癌症相关途径。来自11个剪接事件的风险评分似乎与MDS预后和AML转化独立相关，表明MDS中剪接模式改变的潜在临床相关性。
Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders with prevalent mutations in several splicing factors, but the splicing programs linked to specific mutations or MDS in general remain to be systematically defined. We applied RASL-seq, a sensitive and cost-effective platform, to interrogate 5502 annotated splicing events in 169 samples from MDS patients or healthy individuals. We found that splicing signatures associated with normal hematopoietic lineages are largely related to cell signaling and differentiation programs, whereas MDS-linked signatures are primarily involved in cell cycle control and DNA damage responses. Despite the shared roles of affected splicing factors in the 3′ splice site definition, mutations in U2AF1, SRSF2, and SF3B1 affect divergent splicing programs, and interestingly, the affected genes fall into converging cancer-related pathways. A risk score derived from 11 splicing events appears to be independently associated with an MDS prognosis and AML transformation, suggesting potential clinical relevance of altered splicing patterns in MDS.
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影响因子：
11.4
作者：
通讯作者：
--
影响因子：
16.6
作者：
Liu, Jinfeng;McCleland, Mark;Stawiski, Eric W.;Gnad, Florian;Mayba, Oleg;Haverty, Peter M.;Durinck, Steffen;Chen, Ying-Jiun;Klijn, Christiaan;Jhunjhunwala, Suchit;Lawrence, Michael;Liu, Hanbin;Wan, Yinan;Chopra, Vivek;Yaylaoglu, Murat B.;Yuan, Wenlin;Ha, Connie;Gilbert, Houston N.;Reeder, Jens;Pau, Gregoire;Stinson, Jeremy;Stern, Howard M.;Manning, Gerard;Wu, Thomas D.;Neve, Richard M.;de Sauvage, Frederic J.;Modrusan, Zora;Seshagiri, Somasekar;Firestein, Ron;Zhang, Zemin
通讯作者：
Zhang, Zemin
影响因子：
16.6
作者：
Madan, Vikas;Kanojia, Deepika;Li, Jia;Okamoto, Ryoko;Sato-Otsubo, Aiko;Kohlmann, Alexander;Sanada, Masashi;Grossmann, Vera;Sundaresan, Janani;Shiraishi, Yuichi;Miyano, Satoru;Thol, Felicitas;Ganser, Arnold;Yang, Henry;Haferlach, Torsten;Ogawa, Seishi;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
影响因子：
28.2
作者：
Chen, Justin;Hackett, Christopher S.;Weiss, William A.
通讯作者：
Weiss, William A.
影响因子：
17.1
作者：
Koscielny, Serge
通讯作者：
Koscielny, Serge