Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome

• DOI: 10.1016/j.ccell.2015.04.007
• Publication Date: 2015-05-11T11:45:16Z
• Authors: Simona Colla; Derrick Sek Tong Ong; Yamini Ogoti; Matteo Marchesini; Nipun A. Mistry; Karen Clise-Dwyer; Sonny A. Ang; Paola Storti; Andrea Viale; Nicola Giuliani; Kathryn Ruisaard; Irene Ganan Gomez; Christopher A. Br...; Marcos Estecio; David C. Weksberg; Yan Wing Ho; Baoli Hu; Giannicola Genovese; Piergiorgio Petta...; Asha S. Multani; Shan Jiang; Sujun Hua; Michael C. Ryan; Alessandro Carugo; Luigi Nezi; Yue Wei; Hui Yang; Marianna D’Anca; Li Zhang; Sarah Gaddis; Ting Gong; James W. Horner; Timothy P. Heffernan; Philip Jones; Laurence J.N. Cooper; Han Liang; Hagop Kantarjian; Y. Alan Wang; Lynda Chin; Carlos Bueso-Ramos; Guillermo Garcia-...; Ronald A. DePinho
• Keywords: 0301 basic medicine; Cancer Research; Serine-Arginine Splicing Factors; Animal; RNA Splicing; Myelodysplastic Syndrome; Nuclear Proteins; Cell Differentiation; Ribonucleoprotein; Cell Biology; Haploinsufficiency; Telomere; Hematopoiesis; Mice; 03 medical and health sciences; Oncology; Ribonucleoproteins; Myelodysplastic Syndromes; Animals; Humans; Hematopoiesi; Human; Nuclear Protein

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.