Activation of proto-oncogenes by disruption of chromosome neighborhoods
Author(s)
Hnisz, D.; Day, D. S.; Valton, A.-L.; Bak, R. O.; Goldmann, J.; Lajoie, B. R.; Sigova, A. A.; Lee, T. I.; Porteus, M. H.; Dekker, J.; Weintraub, Abraham Selby; Li, Charles Han; Reddy, Jessica; Borges-Rivera, Diego Ramon; Jaenisch, Rudolf; Fan, Zi Peng; Young, Richard A.; ... Show more Show less
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Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether 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 nonmalignant 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.
Date issued
2015-11Department
Massachusetts Institute of Technology. Computational and Systems Biology Program; Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical ResearchJournal
Science
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Hnisz, D. et al. “Activation of Proto-Oncogenes by Disruption of Chromosome Neighborhoods.” Science 351.6280 (2016): 1454–1458.
Version: Author's final manuscript
ISSN
0036-8075
1095-9203