Robert Bradley, Ph.D.
2015 Grant Recipient
Biological mechanisms and therapeutic opportunities for MOS with spliceosomal mutations
Basic Science Research Grant 2015
Myelodysplastic syndromes (MDS) are a group of blood disorders characterized by inefficient blood production. Currently, the prognosis for MDS is generally poor and there are few effective therapies for the majority of MDS patients. A central reason that few treatment options are available is that our understanding of MDS biology is incomplete. Thanks to a recent research breakthrough, we now know that most cases of MDS are due to genetic mutations that affect a molecular process called RNA splicing, wherein genetic information is read from DNA and used to make proteins. However, despite this recent rapid progress in our understanding of the molecular basis of MDS, we do not yet understand why abnormal RNA splicing results in MDS.
We used a combination of experimental and computational approaches to study how mutations that affect RNA splicing contribute to MDS. We compared and contrasted the consequences of mutations affecting different RNA splicing factors in order to find splicing changes that promote disease. We also identified molecular pathways that are particularly important for the survival of MDS cells with splicing factor mutations. We may be able to create new therapies for MDS by targeting those molecular pathways with drugs. The long-term goal of this research is to understand how different mutations affecting RNA splicing cause MDS, and use that knowledge to identify new therapies.
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
Fei DL, Motowski H, Chatrikhi R, Prasad S, Yu J, Gao S, Kielkopf CL, Bradley RK, Varmus H, Wild-type U2AF1 antagonizes the splicing program characteristic of U2AF1-mutant tumors and is required for cell survival, PLoS Genetics 2016, 12(10):e1006384