Alterations in epigenetic landscape, together with genetic changes, are key events in initiation, progression and drug resistance of human cancers. The research focus of the Wen Laboratory is to delineate how cancer cells, particularly in pediatric cancers, exploit chromatin machinery to activate oncogenic or silent tumor suppressive gene expression programs, with the long-term goal of developing therapies to target epigenomic or epigenetic regulators for cancer treatment.
One of the lab’s current research projects is to characterize the role of ENL/MLLT1 in MLL-rearranged leukemia and other pediatric cancers. MLL-rearranged leukemia is a subtype of acute leukemia caused by MLL gene translocation, which accounts for about 70 percent of pediatric leukemia cases. Their previous work has identified the YEATS domain as a novel reader of histone acetylation (Li and Wen et al, Cell 2014) and uncovered that the ENL YEATS domain is critical for the expression of essential genes for disease maintenance in MLL-rearranged leukemia (Wan and Wen et al, Nature 2017). The lab is currently characterizing the role of ENL and its YEATS domain in tumor initiation and maintenance in a broad range of pediatric leukemias. We are also working on development of small molecules targeting the YEATS domain of ENL.
The ENL YEATS domain is frequently mutated in Wilms tumor, the most common pediatric kidney cancer. Another of the lab’s project is to investigate the molecular mechanism by which the ENL mutations contribute to Wilms tumor oncogenesis.
Dr. Wen and her team also study tumor suppressor ZMYND11, an adenovirus E1A-binding protein. She has previously identified that ZMYND11 is a bona-fide histone variant H3.3-specific reader of H3K36 methylation that regulates transcription elongation (Wen et al, Nature 2014). Her lab is now generating a knockout mouse model to determine the role of ZMYND11 in tumor suppression in vivo.