| Literature DB >> 25965571 |
Simona Colla1, Derrick Sek Tong Ong2, Yamini Ogoti3, Matteo Marchesini3, Nipun A Mistry4, Karen Clise-Dwyer5, Sonny A Ang6, Paola Storti7, Andrea Viale2, Nicola Giuliani8, Kathryn Ruisaard5, Irene Ganan Gomez3, Christopher A Bristow9, Marcos Estecio10, David C Weksberg2, Yan Wing Ho2, Baoli Hu2, Giannicola Genovese2, Piergiorgio Pettazzoni2, Asha S Multani11, Shan Jiang2, Sujun Hua2, Michael C Ryan12, Alessandro Carugo2, Luigi Nezi2, Yue Wei3, Hui Yang3, Marianna D'Anca3, Li Zhang4, Sarah Gaddis13, Ting Gong13, James W Horner9, Timothy P Heffernan9, Philip Jones9, Laurence J N Cooper6, Han Liang4, Hagop Kantarjian3, Y Alan Wang2, Lynda Chin2, Carlos Bueso-Ramos14, Guillermo Garcia-Manero3, Ronald A DePinho15.
Abstract
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.Entities:
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Year: 2015 PMID： 25965571 PMCID： PMC4596059 DOI： 10.1016/j.ccell.2015.04.007
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743