Dr. Yang's project is Structural insights into deregulated epigenetic mechanisms and DNA demethylation in MDS. The exciting new discovery of frequent Tet2 mutation mutation: Any change or alteration in a gene. A mutation may cause disease or may be a normal variation. Paroxysmal nocturnal hemoglobinuria (PNH) occurs because of a mutation in the PIG-A gene of a single stem cell in the bone marrow. in a wide range of myeloid malignancies including myelodysplastic syndromes myelodysplastic syndromes: (my-eh-lo-diss-PLASS-tik SIN-dromez) A group of disorders where the bone marrow does not work well, and the bone marrow cells fail to make enough healthy blood cells. Myelo refers to the bone marrow. Dysplastic means abnormal growth or development. People with MDS have low blood cell count for at… (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 bone marrow failure: A condition that occurs when the bone marrow stops making enough healthy blood cells. The most common of these rare diseases are aplastic anemia, myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH). Bone marrow failure can be acquired (begin any time in life) or can be… 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 bone marrow: The soft, spongy tissue inside most bones. Blood cells are formed in the bone marrow. function. Towards this aim, we have begun to analyze a myelodysplastic syndromes myelodysplastic syndromes: (my-eh-lo-diss-PLASS-tik SIN-dromez) A group of disorders where the bone marrow does not work well, and the bone marrow cells fail to make enough healthy blood cells. Myelo refers to the bone marrow. Dysplastic means abnormal growth or development. People with MDS have low blood cell count for at… (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.