Activation of proto-oncogenes by disruption of chromosome neighborhoods
Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Biochemistry | Cancer Biology | Genetics and Genomics | Molecular Biology | Structural Biology | Systems Biology
Oncogenes are activated through well-known chromosomal alterations, including gene fusion, translocation and focal amplification. Recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods led us to investigate whether proto-oncogenes occur within these structures and if oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T-cell acute lymphoblastic leukemia (T-ALL), and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in non-malignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.
DOI of Published Version
Science. 2016 Mar 3. pii: aad9024. Link to article on publisher's site
Science (New York, N.Y.)
Hnisz, Denes; Weintraub, Abraham S.; Day, Daniel S.; Valton, Anne-Laure; Bak, Rasmus O.; Li, Charles H.; Goldmann, Johanna; Lajoie, Bryan R.; Fan, Zi Peng; Sigova, Alla A.; Reddy, Jessica; Borges-Rivera, Diego; Lee, Tong Ihn; Jaenisch, Rudolf; Porteus, Matthew H.; Dekker, Job; and Young, Richard A., "Activation of proto-oncogenes by disruption of chromosome neighborhoods" (2016). Program in Systems Biology Publications and Presentations. 81.