Dr. Christopher Denny's research focuses on genomic mutation as a primary force in the genesis of human malignancy. Molecular isolation of genes involved in tumor-specific rearrangements has identified mechanisms of tumorigenesis and has formed a basis for studying transformation pathways of human cancers.
Denny's lab has focused specifically on the 11:22 translocation that occurs in Ewing's sarcoma and PNET, two lethal and poorly understood pediatric cancers of presumed neural crest origin. This rearrangement fuses a previously unknown gene, termed EWS, to FLI-1, a member of the ETS family of transcription factors. Denny's lab has isolated this chimeric molecule both as genomic and cDNA clones, and has shown that EWS/FLI can transform rodent fibroblast lines. This is consistent with the notion that it plays an active role in Ewing's sarcoma oncogenesis.
Mutation analyses, DNA-binding studies, and subcellular localization experiments have led Denny and his colleagues to hypothesize that EWS/FLI is acting as an aberrant transcription factor that is qualitatively different from normal FLI-1. A novel method for identifying differentially expressed genes has been developed to isolate potential target genes that are modulated by EWS/FLI. This cohort of EWS/FLI regulated genes is now being analyzed with a long-term goal of defining important genetic pathways that are activated during cellular transformation.
Selected Cancer-Related Publications:
Ng KP, Potikyan G, Savene RO, Denny CT, Uversky VN, Lee KA. Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins. Proc Natl Acad Sci U S A. 2007; 104(2): 479-84.
Deneen B, Hamidi H, Denny CT. Functional analysis of the EWS/ETS target gene uridine phosphorylase. Cancer Res. 2003; 63(14): 4268-74.
Deneen B, Welford SM, Ho T, Hernandez F, Kurland I, Denny CT. PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins. Mol Cell Biol. 2003; 23(11): 3897-908.