MERIT Award Recipient: Daniel A. Haber, M.D., Ph.D.
Functional Properties of the Wilm's Tumor Gene WT1
Dr. Haber has received a MERIT award for his work on the pediatric kidney cancer Wilms Tumor. Wilms Tumor is a cancer originating in renal precursor cells that has been linked to the inactivation of the WT1 gene, encoding a zinc finger transcription factor with multiple alternatively spliced isoforms. Expression of WT1 is required for development of the kidney, gonads, and some mesothelial tissues. Germline mutations in WT1 result in genetic predisposition to Wilms Tumor; somatic mutations of WT1 are also present in a subset of sporadic tumors.
Dr. Haber's laboratory has developed approaches to identify transcriptional targets of WT1 as a way to uncover the signaling pathways that are regulated by WT1. By using cells with tightly regulated inducible expression of different WT1 isoforms to interrogate high density oligonucleotide microarrays, the laboratory has identified a number of WT1 target genes. These genes (such as amphiregulin) have been shown to be transcriptionally regulated by WT1 and their physiological significance is supported by temporal and spatial coexpression with WT1 during renal differentiation and by their effects in organ culture assays. The MERIT award will be used to extend this strategy to different isoforms of WT1 whose functional properties are not well understood (such as the WT1(+KTS) isoform), as well as to other transcription factors that play essential roles in kidney differentiation (such as the BF2 forkhead/winged helix family member). Taken together, these studies will combine molecular characterization of transcription factor targets identified by microarray screens with biological assays of kidney differentiation, providing insight into the mechanisms that drive malignant transformation of kidney precursor cells.