Stephanie Halene, M.D., Ph.D.
2014 Grant Recipient
Molecular mechanisms underlying deregulated hematopoiesis caused by mutations in the serine-rich splicing factor 2 (SRSF2) in myelodysplasia (MDS)
Basic Science Research Grant 2014
Myelodysplasia is a disease of the blood stem cells that make all the blood cells in the body. With aging the stem cells acquire mutations in select genes resulting in their abnormal function. Such mutations affect many subclasses of genes critical to basic function of the cell. One class of such genes contains the splicing factors, proteins that process all messages, the RNA, in the cell that relay the information from the genome to the protein making machinery. Our laboratory focuses specifically on one splicing factor, SRSF2 (serine/arginine rich splicing factor 2), that is mutated in over 30% of patients with myelodysplasia. We specifically explored the mechanism, by which mutations in SRSF2 alter its normal function, and thereby result in the formation of abnormal blood cells. We show that mutations alter the structure of SRSF2 such that it binds RNA with different affinity and specificity compared to un-mutated SRSF2. We show that this abnormal binding is preserved in the context of the cell, in vivo, resulting in abnormal binding to and processing of RNA. We have identified targets of alternative splicing by wildtype and mutant SRSF2 whose splice isoforms may significantly alter key cellular processes. These studies will contribute to our understanding of how genetic mutations in splicing factors cause MDS and set the stage for the development of therapeutics.
Eunhee Kim, Janine O. Ilagan, Yang Liang, Gerrit M. Daubner, Stanley C.-W. Lee, Aravind Ramakrishnan, Yue Li, Young Rock Chung, Jean-Baptiste Micol, Michele E. Murphy, Hana Cho, Min-Kyung Kim, Ahmad S. Zebari, Shlomzion Aumann, Christopher Y. Park, Silvia Buonamici, Peter G. Smith, H. Joachim Deeg, Camille Lobry, Iannis Aifantis, Yorgo Modis, Frederic H.-T. Allain, Stephanie Halene, Robert K. Bradley, and Omar Abdel-Wahab, SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition, Cancer Cell 2015, 27, 617-630. doi: 10.1016/j.ccell.2015.04.006
Joshi, P., Halene, S., and Abdel-Wahab, O. (2017). How do messenger RNA splicing alterations drive myelodysplasia? Blood 129, 2465-2470