Investigating and targeting the histone acetylation reader protein ENL in acute leukemias
Hong Wen
PhDVan Andel Research Institute
Project Term: July 1, 2022 - June 30, 2027
Leukemia often results from aberrant gene expression caused by epigenetic alterations. Previously we discovered a novel histone acetylation reader domain in the ENL protein and demonstrated that this domain is essential for the survival of a wide range of acute leukemias, making it an attractive therapeutic target. We will develop specific inhibitors of ENL activity in acute leukemias and will use mouse models to define the role of ENL mutations identified in patients in leukemogenesis.
Leukemia, a blood cancer, is a complexed disease. Some leukemias are readily treated and have excellent prognosis, while other leukemias, such as acute myeloid leukemia (AML) and mixed-lineage leukemia (MLL), still have dismal outcomes with standard treatments. We therefore seek to understand the origin and pathogenesis of these specific leukemia subtypes so that we can identify novel therapeutic targets and develop new types of drugs or interventions.
Cancers, including leukemias, are often caused by genetic mutations of genes. Among the genetic alterations identified in leukemias, we are particularly interested in the ones causing malfunctions of epigenetic regulators. In the nuclei of cells, DNA is wrapped around histone proteins in a structure called chromatin. Chromatin can be densely packed or relatively open. Only when chromatin is open, DNA is accessible for activities such as DNA transcription, replication, or repair. Epigenetic regulators are key players in controlling chromatin status and DNA accessibility. Mutations of epigenetic regulators are frequently found in human cancers, therefore epigenetic regulators are often attractive therapeutic targets.