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Science. 2016 Mar 25;351(6280):1454-1458. doi: 10.1126/science.aad9024. Epub 2016 Mar 3.

Activation of proto-oncogenes by disruption of chromosome neighborhoods.

Author information

1
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
2
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
3
Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
4
Department of Pediatrics, Stanford University, Stanford, California, USA.
5
Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
6
Howard Hughes Medical Institute.
#
Contributed equally

Abstract

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.

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PMID:
26940867
PMCID:
PMC4884612
DOI:
10.1126/science.aad9024
[Indexed for MEDLINE]
Free PMC Article

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