Omar Abdel-Wahab, M.D., Ph.D.
2014 Grant Recipient
Molecular and Biological Consequence of SRSF2 Mutations in the Myelodysplastic Syndromes
Basic Science Research Grant 2014
Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by inefficient blood production. There are few effective therapies for the majority of MDS patients. An important reason that relatively few therapies are available is that we have an incomplete understanding of why and how MDS develops. In 2011, researchers discovered that most patient with MDS carry genetic mutations that spontaneously developed in the bone marrow, ultimately affecting a process called RNA splicing. RNA splicing is the process wherein genetic information is read from DNA and then used to make proteins. However, despite these research breakthroughs in determining the set of genetic mutations that are associated with MDS, we do not yet fully understand why abnormal RNA splicing results in MDS. Thus, the goals of our EvansMDS proposal were to determine how spliceosomal gene mutations result in the development of MDS in more detail. We have since identified that mutations in the spliceosomal gene SRSF2 change the function of this gene in a manner that alters its ability to recognize RNA. This results in a host of splicing and gene expression changes in cells, which ultimately cause MDS to develop. In fact, we found that expression of the MDS-associated SRSF2 mutations in the blood cells of mice directly causes a disease like MDS to develop in the animals. We are now using these models and the insights on how SRSF2 mutation effects RNA splicing to develop therapies targeting cells carrying abnormal SRSF2. Our hope is that this effort will result in new therapies for patients with MDS.
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
Stanley Chun-Wei Lee, Heidi Dvinge, Eunhee Kim, Hana Cho, Jean-Baptiste Micol, Young Rock Chung, Benjamin H Durham, Akihide Yoshimi, Young Joon Kim, Michael Thomas, Camille Lobry, Chun-Wei Chen, Alessandro Pastore, Justin Taylor, Xujun Wang, Andrei Krivtsov, Scott A Armstrong, James Palacino, Silvia Buonamici, Peter G Smith, Robert K Bradley & Omar Abdel-Wahab, Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins, Nature Medicine 2016, 22, 672. doi: 10.1038/nm.4097
Heidi Dvinge, Eunhee Kim, Omar Abdel-Wahab and Robert K. Bradley, RNA splicing factors as oncoproteins and tumour suppressors, Nature Reviews Cancer 2016, 16, 413. doi: 10.1038/nrc.2016.51
Daichi Inoue, Robert K. Bradley, and Omar Abdel-Wahab, Spliceosomal gene mutations in myelodysplasia: molecular links to clonal abnormalities of hematopoiesis, Genes & Development 2016, doi: 10.1101/gad.278424
Dr. Abdel-Wahab received the Joanne Levy Memorial Award at the 57th Annual Meeting of the American Society of Hematology in December of 2015 for work supported in part by the Edward P. Evans Foundation.