David Sweetser, MD, PhD
Dr. Sweetser received his B.S. in Biological Science with Honors from Stanford University in 1982, his M.D./Ph.D. at Washington University in St. Louis, followed by a Pediatric Residency at St. Louis Children’s Hospital, Clinical Genetics and Biochemical Genetics Fellowships at Washington University and the University of Washington in Seattle. He then completed a postdoctoral fellowship with Richard Palmiter, and a Pediatric Hematology/Oncology Fellowship at Seattle Children’s Hospital. He started a Research Program in Leukemia Genetics at Fred Hutchinson Cancer Research Center where he Attended on the Bone Marrow Transplant Service prior to moving to MGH in 2003. He continues clinical work in Pediatric Hematology/Oncology as well as in Medical Genetics and became Chief of the Division of Medical Genetics and Metabolism at MGH in 2011.
Questions being addressed in the lab
- The Sweetser laboratory investigates how leukemia and other cancers develop with the goal of developing novel, safer, and more effective therapies. His work identified the Groucho/TLE family of co-repressors as gatekeepers preventing the development of leukemia by oncogenes such as AML1-ETO. His lab continues to study how these TLEs function as potent tumor suppressors of acute myeloid leukemia and their roles in normal development and cell function.
- His lab and clinical research team is also actively engaged in clinical and research work using whole exome and whole genome sequencing for diagnosis and new gene discovery and collaborating with researchers at MGH and around the world. Dr. Sweetser is the MGH Site Director for the Undiagnosed Diseases Network.
- Dr. Sweetser together with Dr. Ronald Thibert, started the world’s first Pitt Hopkins Syndrome Clinic at MGH. This genetic syndrome is caused by mutations in the TCF4 gene involved in Wnt signaling. In collaborations with Stephen Haggerty in the CHRC and Brady Maher from The Lieber Institute for Brain Development in Baltimore we are evaluating potential biomarkers and biophysical parameters in these patients to be used in developing clinical trials of agents promising for the treatment of this and potentially other autism spectrum disorders.
Projects underway to answer these questions
A variety of experiments in the laboratory have demonstrated how loss of the TLE genes leads to hematopoietic cell proliferation and cooperates with oncogenes to cause leukemia.
Conditional knockout mice for Tle1 and Tle4 were created to better understand the role of these genes in normal developmental and cancer.
The Harvard Medical School hospital consortium of MGH, Brigham and Women’s Hospital and Children’s Hospital has been recently selected as one of six new sites comprising a nationwide Undiagnosed Diseases Network. As Chief of Medical Genetics at MGH, and the MGH site director for the UDN, Dr. Sweetser is coordinating a team of expert clinicians and researchers, and is using whole exome and whole genome sequencing, and a variety of investigative resources to identify the underlying basis of a variety of challenging human diseases.
Tle1 deficient mice produce enhanced inflammatory response to TPA treatment. These experiments identified Tle1 as a previously unrecognized major regulator of inflammation.
Tle 4 is not only a tumor suppressor gene in AML, but is critical for normal bone mineralization and bone marrow support.
Knock-out mice for Tle1 and Tle4 have identified critical roles for these proteins in hematopoiesis, bone, lung, and brain development, as well as a critical role in limiting inflammation. We have defined critical inflammatory signaling pathways mediating cell proliferation and synergistic cross talk of leukemic cells and the cancer niche.
Highlighted Publications from the lab
Tle1 tumor suppressor negatively regulates inflammation in vivo and modulates NF-κB inflammatory pathway