Colla Simona, Ong Derrick Sek Tong, Ogoti Yamini, Marchesini Matteo, Mistry Nipun A, Clise-Dwyer Karen, Ang Sonny A, Storti Paola, Viale Andrea, Giuliani Nicola, Ruisaard Kathryn, Ganan Gomez Irene, Bristow Christopher A, Estecio Marcos, Weksberg David C, Ho Yan Wing, Hu Baoli, Genovese Giannicola, Pettazzoni Piergiorgio, Multani Asha S, Jiang Shan, Hua Sujun, Ryan Michael C, Carugo Alessandro, Nezi Luigi, Wei Yue, Yang Hui, D'Anca Marianna, Zhang Li, Gaddis Sarah, Gong Ting, Horner James W, Heffernan Timothy P, Jones Philip, Cooper Laurence J N, Liang Han, Kantarjian Hagop, Wang Y Alan, Chin Lynda, Bueso-Ramos Carlos, Garcia-Manero Guillermo, DePinho Ronald A
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Cell. 2015 May 11;27(5):644-57. doi: 10.1016/j.ccell.2015.04.007.
Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation.
骨髓增生异常综合征（MDS）的风险与年龄增长、治疗诱导的DNA损伤和/或较短的端粒相关，但端粒侵蚀是否直接诱发MDS尚不清楚。在此，我们提供了遗传学证据，表明端粒功能障碍诱导的DNA损伤驱动经典的MDS表型，并通过抑制包括SRSF2在内的mRNA剪接/加工基因的表达来改变常见髓系祖细胞（CMP）的分化。对端粒功能障碍的CMP进行RNA测序分析，确定了与MDS发病机制相关途径（如基因组稳定性、DNA修复、染色质重塑和组蛋白修饰）相关的异常剪接转录本，这些转录本在SRSF2单倍体不足的小鼠CMP以及携带SRSF2突变的CD34(+) CMML患者细胞中也有富集。总之，我们的研究在端粒生物学、异常RNA剪接和髓系祖细胞分化之间建立了紧密的联系。
