Bernt Laboratory

Project Highlights

• IDH Mutations: IDH mutations occur in 15 percent of adult AML. These mutations are mutually exclusive with inactivating mutations of the TET2 enzyme, which convers DNA methylcytosin to hydroxymethylcytosin. The canonical mechanism of mutant IDH induced leukemogenesis involved the production of massively increased levels of the “oncometabolite” 2HG, which inhibits TET2 enzymatic function. However, 2HG also inhibits a number of histone demethylases. Data from the Bernt Lab suggests that this chromatin pathway may be functionally relevant. The lab uses retroviral and knock-in murine models with different co-drivers and patient samples to investigate the role of aberrant histone methylation in IDH-mutant AML.
• Meningioma-1 (MN1): MN1 is a poorly characterized transcriptional co-activator that serves as a fusion partner in MN1-TEL and MN1-FLI1 fusions in AML. It is also commonly overexpressed in AML. MN1 fusions as well as wild type MN1 are strongly oncogenic, however, the mechanism of leukemogenesis is poorly understood. The lab uses a broad approach involving syngeneic murine models, cell lines, and patient samples as well as genomic/epigenomic/transcriptomic and proteomic approaches to uncover the molecular mechanism by which fusions and wild type MN1 cause leukemia, with the hope of identifying targeted therapeutic agents.
• Inv(16) AML: Inv(16) are found fairly frequently in children and adults with AML. Although considered a “good risk subtype,” almost 30 percent of children and 50 percent of adults still relapse, suggesting a need for improved therapeutic approaches. One hundred percent of inv(16) AML overexpress MN1. The Bernt Lab is studying the role of MN1, as well as additional epigenetic abnormalities in inv(16) AML, using a genetic knock-in mouse model, cell lines, and patient samples.
• Developmental pathways: The Bernt Lab is working to uncover developmental pathways during early childhood bone marrow development that are aberrantly regulated in leukemia. For this line of investigation the lab team uses single-cell analysis of normal and malignant patient-derived bone marrow cells.