The Molecular Basis of Genomic Instability: A Genome Wide Approach

Type of Award: Catalyst
Date Awarded: January 2011
Award End Date: December 2012
Amount Awarded: $ 200,000.00
PI(s): Steven T. Rosen, MD, NU; Fotini Gounari, PhD, UChicago;

Abstract: Cancer cells have unstable genomes and show significant diversions from normal cells. These include major alterations in the copy number of chromosomes, translocations of parts of a chromosome to another as well as local inversions of chromosomes. Major and smaller scale cryptic changes are present in almost all cancers. Their link to carcinogenesis is best established in leukemia/lymphoma, where specific translocations and the resulting activation of cancer genes have been characterized in detail. Certain translocations occur recurrently indicating that specific chromosomal loci are either selectively targeted or selected during transformation. How are these loci chosen and what molecular mechanisms are involved is unclear. Our hypothesis is that genomically unstable cancers share similar underlying molecular mechanisms, which can be revealed by distinct gene expression properties. The study of these mechanisms requires experimental models that are marked by spontaneous translocations. We have developed an animal model in which genomically unstable T-cell lymphomas show identical translocations to those seen in human leukemia/lymphoma. This model allows us to determine genome wide transcription and chromatin changes that are associated with the state of genomic instability. The findings will be related to human cancer through a collaboration between our two laboratories at the University of Chicago and Northwestern University. These studies will help us understand the mechanisms responsible for genomic instability in cancer and in particular in hematologic malignancies, providing new opportunities for therapeutic intervention.

Dr. Rosen is the director of the Northwestern Comprehensive Cancer Center and an international authority in T-cell lymphomas. Dr. Gounari, an immunologist at the University of Chicago, has developed and characterized the animal model and the preliminary work on translocations in leukemia/lymphoma.