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<P><SPAN STYLE="font-family: georgia, palatino; font-size: small; color: #000000;"><STRONG>Title:</STRONG>RNA splicing as a new mechanism of oncogenesis</SPAN></P>
<P><SPAN STYLE="font-family: georgia, palatino; font-size: small; color: #000000;">Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis. Biography: Dr. Bradley studies RNA biology in human disease, with a focus on identifying new roles for abnormal RNA processing in disease initiation and therapeutic response. Two areas of current interest are mutations affecting RNA splicing factors in myelodysplastic syndromes and nonsense-mediated decay in facioscapulohumeral muscular dystrophy. Dr. Bradley is also broadly interested in methods to combine and analyze high-throughput sequencing data from research and clinical settings.</SPAN></P>
<P><SPAN STYLE="font-family: georgia, palatino; font-size: small; color: #000000;"><SPAN STYLE="text-decoration: underline;">Robert Bradley</SPAN> is a <EM>Principal Investigator</EM> at the Fred Hutchinson Cancer Research Center. His lab<SPAN STYLE="line-height: 1.6em;">studies</SPAN><SPAN STYLE="line-height: 20px;">many different disorders - from muscular dystrophy to cancer - where RNA processing plays important roles in disease initiation and therapeutic response. In the long term, we seek to identify new biological phenomena that inform the development of improved treatments and therapeutics.</SPAN></SPAN></P>
<P><SPAN STYLE="font-family: georgia, palatino; font-size: small; color: #000000;"><SPAN STYLE="line-height: 20px;"><SPAN STYLE="text-decoration: underline;">Omar Abdel-Wahab</SPAN> is a<SPAN STYLE="line-height: 22px;"><EM>Physician-Scientist</EM> at Memorial Sloan Kettering Cancer Center. His lab studies the functional genomics of hematopoietic malignancies.</SPAN></SPAN></SPAN></P>
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