Dr. Yang's project is Structural insights into deregulated epigenetic mechanisms and DNA demethylation in MDS. The exciting new discovery of frequent Tet2 mutation in a wide range of myeloid malignancies including myelodysplastic syndromes (MDS) highlights the clinical significance of this myeloid relevant protein with potential applications to disease diagnosis, treatment, and prognosis. Successful completion of this project that focuses on Tet2 structure and function will be important for unraveling the structural basis of MDS at the molecular level, providing a framework for understanding how pathological Tet2 mutations cause MDS, and most importantly, will potentially open avenues to novel therapeutic strategies to ameliorate a variety of myeloid disorders including MDS. "This project will have a major impact in a broad area of bone marrow failure research, including our understanding of how MDS develops and new therapeutic strategies for MDS and other myeloid disorders."
Our long term goal is to understand the molecules and mechanisms that regulate normal generation of blood cellular components as well as malignant cell transformation, as a necessary prerequisite of discovering factors that could fine-tune blood cell differentiation or restore normal bone marrow function. Towards this aim, we have begun to analyze a myelodysplastic syndromes (MDS)-associated protein and a large panel of disease-causing mutants. We found some of the mutations, which are associated with the most severe diseases in humans, caused significant decrease in the protein’s DNA binding activity, while the activities of the other mutant proteins were not significantly different from wild type protein. More interestingly, the catalytic domain of wild type protein was observed to unfold in a single-step, highly cooperative manner; in contrast, most of mutant proteins were significantly more prone to thermal denaturation and aggregation. These results are significant because they will have significant impacts on design of mutant-specific rescue drugs: for instance, second-site suppressor or chaperone strategy often used for rescuing mutant function can be implemented for rescue of destabilized protein mutant. On the other hand, the forthcoming protein three-dimensional structure can be instantly applied to structure-based drug design or in silico screening of mutanttargeting compounds.