DSRCT Research

Research
Not enough!!!

Institutes and Foundations
Stehlin Foundation


 * NIDDK, National Institutes of Health
 * Sean Bong Lee, Ph.D. Sean Bong Lee, Ph.D.
 * Genetics of Development and Disease Branch
 * Building 10, Room 9N313
 * Bethesda, MD 20892
 * Tel:301-496-9739
 * Fax:301-480-0638
 * Email: SeanL@intra.niddk.nih.gov


 * B.S., SUNY at Buffalo, 1989
 * Ph.D., SUNY Health Science Center at Brooklyn, 1994

Research Statement The primary interest of this laboratory is to understand how perturbations during normal development process can lead to cancer. In particular, Wilms' tumor, a childhood kidney cancer, serves as a paradigm for studying development and cancer in our laboratory.

The Wilms' tumor suppressor gene, WT1, is mutated in 10-15% of Wilms' tumor and it encodes a transcription factor with four C2H2 zinc fingers as its DNA binding domain. In addition to Wilms' tumor, mutations inWT1 are found in other human diseases such as WAGR, Danys-Drash and Frasier syndromes, all of which display developmental defects in both kidneys and gonads. WAGR and Danys-Drash patients also suffer from an increased risk of Wilms' tumor. WT1 is proposed to regulate the transcription of genes that are critical for the initiation and differentiation of kidneys, gonads, spleen, and the adrenal gland since wt1-null mouse embryos lack all of these organs. Our laboratory is focused on the identification of WT1 target genes that initiate and coordinate organogenesis of the kidney and other affected tissues, as well as identifying WT1-containing complexes. We are using microarray and chromatin-IP techniques to identify and verify potential WT1-target genes. Identification of the target genes and defining their role during development will provide further insights to the development of Wilms' tumor and organogenesis in general.

Ewing's sarcoma and related small round cell tumors have a distinct characteristic which involves chromosomal translocation of the Ewing's sarcoma gene (EWS) to various transcription factor-encoding genes. The prototype is the EWS/Fli-I translocation found in about 80% of Ewing's sarcoma. Desmoplastic small round cell tumor (DSRCT) is another example of chromosomal translocation that leads to the fusion of EWS gene to the WT1 gene. Current treatment for DSRCT is minimally effective and the pathways that are responsible for generating the tumor are largely undefined. To identify the mechanisms of tumorigenesis in DSRCT, we are attempting to generate a mouse model of DSRCT by expressing the EWS/WT1 gene product in mouse embryonic stem cells. The mouse model, if successful, will then be used to dissect molecular pathways that are responsible for the formation of DSRCT, which can lead to the development of new therapeutics against DSRCT-specific molecular targets.