The Ebert laboratory is based at Brigham and Women’s Hospital, with links to the Dana-Farber Cancer Institute, Broad Institute, and Harvard Stem Cell Institute. The primary focus of the laboratory is the biology and treatment of hematologic malignancies, with a particular focus on myelodysplastic syndrome.
Genetic dissection of myeloid malignancies
Myelodysplastic syndrome (MDS) is a hematologic malignancy characterized by abnormal differentiation and a deficiency of mature blood cells. We are interested in identifying and characterizing the somatic mutations that cause MDS. In large-scale genetic analyses of patient samples, the lab has identified somatic mutations that predict prognosis and response to therapies in MDS patients, characterized a pre-malignant state of hematopoietic cells, and derived the molecular ontogeny of genetic lesions in myeloid malignancies.
Biological basis of myeloid malignancies
In addition to human genetic studies, the lab studies the biological basis of transformation of hematopoietic cells by somatic mutations. The lab applies a range of technologies, including genomics and proteomic approaches in combination with classical cell and molecular biology. The lab has developed novel in vivo models to study myeloid malignancies, including the use of CRISPR/Cas9 genome engineering to create new leukemia models. We employ genetic screens to identify novel therapeutic targets for the treatment of hematologic malignancies.
Therapeutic targeting of E3 ubiquitin ligases
The Ebert lab elucidated the mechanism of action of lenalidomide, a derivative of thalidomide. Lenalidomide and related drugs modulate the function of an E3 ubiquitin ligase, inducing drug-dependent degradation of specific substrates that are essential for the survival of multiple myeloma and MDS cells. Thalidomide, lenalidomide, and related compounds are therefore the first drugs that bind and modulate the function of an E3 ubiquitin ligase.
Development of new treatments for sickle cell disease
We are working on novel therapies that induce the expression of fetal hemoglobin for the treatment of sickle cell disease. Sickle cell disease is caused by a mutation in the beta globin gene that causes hemoglobin to polymerize in red blood cells, resulting in stiff, abnormally shaped red blood cells that can occlude the microvasculature. Induction of the fetal form of beta globin has the potential to inhibit the polymerization of sickle hemoglobin, preventing the complications of the disease. We are working to develop small molecules that induce the expression of fetal hemoglobin and to test novel therapies in clinical trials.