Ebert Lab Research

A major focus of the Ebert laboratory is to understand the molecular basis of blood cancers. We investigate the mutations that drive the initiation and progression of myeloid malignancies, and the factors that predict outcome and response to therapy. We characterized clonal hematopoiesis of indeterminate potential (CHIP) and discovered that CHIP, while pre-malignant, increases the risk of not only myeloid malignancies, but also cardiovascular disease and other inflammatory diseases. Our genetic studies have identified somatic mutations in myelodysplastic syndrome (MDS) that predict overall survival and outcome following bone marrow transplantation.  We have generated and characterized a range of models of CHIP and MDS, including the use of CRISPR/Cas9 genome editing of hematopoietic stem and progenitor cells.

Our investigation into the mechanism of action of lenalidomide, a drug with efficacy in hematologic malignancies, particularly MDS and multiple myeloma, revealed that lenalidomide and related compounds act by modulating the function of an E3 ubiquitin ligase, resulting in the highly specific degradation of disease-related proteins.  We have subsequently explored a broader range of protein substrates that can be degraded by lenalidomide and other thalidomide derivatives, and we have elucidated other novel mechanisms of drug-induced protein degradation.  For example, we have characterized a mechanism of drug-induced polymerization of BCL6, a lymphoma oncogene, that results in highly specific ubiquitination and degradation the protein.