Margaret (Peggy) Goodell, Ph.D.
2014 Grant Recipient
Environmental Drivers of MDS in Context of Mutations in Epigenetic Regulators
Basic Science Research Grant 2014
Aging is the biggest risk factor for development of myelodysplastic syndrome (MDS), but the mechanisms through which aging fosters MDS are unclear. We hypothesize that many people acquire genetic mutations in their bone marrow that are common in MDS, but only a subset develop MDS due to particular environmental factors that promote their disease. If we can identify these factors, we may be able to inhibit or slow the disease progression substantially.
This work explored the role of two proteins in ensuring that information in the genome is read and processed correctly. When either of these two proteins, called DNMT3A and TET2, are manufactured with an error, myelodysplastic syndrome can result. Our work sought to uncover how, at a molecular level, this occurs. We deleted the genes for these proteins in mice, either alone or together, and studied the effects in mice and in the way other genes were expressed. We found that many other genes became mis-expressed, especially when we ablated both TET2 and DNMT3A. Our experiments suggest that these proteins are therefore important for setting up an environment that ensures the highly regulated expression of genes throughout the whole genome. These studies will lay the groundwork for more in depth analysis of how the environment promotes MDS, particularly in the context of these common MDS-associated gene mutations.
Mayle, A., Yang, L., Rodriguez, B., Zhou, T., Chang, E., Curry, C.V., Challen, G.A., Li, W., Wheeler, D., Rebel, V.I., et al. (2015). Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation, Blood 125:629-638. DOI: 10.1182/blood-2014-08-594648
Yang, L., Rau, R., and Goodell, M.A. (2015). DNMT3A in Haematological Malignancies, (REVIEW) Nature Reviews Cancer 15:152-165
Rau, RE, Luo, M, Rodriguez, B, Jeong, M, Rosen, A, Campbell, CA, Daigle, S, Deng, L, Song, YC, Sweet, S, Chevassut, T, Kornblau, S, Andreeff, M, Li, W, and MA Goodell (2016) DOT1L as a Therapeutic Target for the Treatment of DNMT3A-Mutant Acute Myeloid Leukemia, Blood 128:971-981
Eckstein OS, Wang, L, Punisa, JN, Kornblau, S, Andreeff, M, Wheeler, DA, Goodell, MA and Rau, RE. (2016) Mixed Phenotype Acute Leukemia (MPAL) Exhibits Frequent Mutations in Epigenetic Regulatory and Splicing Genes, Experimental Hematology 44:740-744. DOI: 10.1016/j.exphem.2016.05.003
Zhang, X, Su, J, Jeong, M, Ko, Mm Huang, Y, Park, HJ, Guzman, A, Lei, Y, Huang, YH, Rao, A, Li, W, and MA Goodell (2016) DNMT3A and TET2 Compete and Cooperate to Repress Lineage-Specific Factors in Hematopoietic Stem Cells, Nature Genetics 48:1014-23.
Gundry, MC, Brunetti, L, Lin, A, Mayle, A, Kitano, A, Wagner, D, Hsu, JI, Hoegenauer, JA, Rooney, C, Goodell, MA, and Nakada, D (2016) Highly Efficient Genome Editing of Murine and Human Hematopoietic Progenitor Cells by CRISPR/Cas9.,(2016) Cell Reports 17: 1453-1461. DOI: 10.1016/j.celrep.2016.09.092