Activation of proto-oncogenes by disruption of chromosome neighborhoods

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Denes Hnisz, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • ,
  • Abraham S Weintraub, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • ,
  • Daniel S Day, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • ,
  • Anne-Laure Valton, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
  • ,
  • Rasmus O Bak
  • Charles H Li, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • ,
  • Johanna Goldmann, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • ,
  • Bryan R Lajoie, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
  • ,
  • Zi Peng Fan, Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • ,
  • Alla A Sigova, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • ,
  • Jessica Reddy, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • ,
  • Diego Borges-Rivera, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • ,
  • Tong Ihn Lee, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
  • ,
  • Rudolf Jaenisch, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • ,
  • Matthew H Porteus, Department of Pediatrics, Stanford University, Stanford, California, USA.
  • ,
  • Job Dekker, Howard Hughes Medical Institute
  • ,
  • Richard A Young, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

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.

Original languageEnglish
JournalScience
Volume351
Issue6280
Pages (from-to)1454-1458
Number of pages5
ISSN0036-8075
DOIs
Publication statusPublished - 25 Mar 2016
Externally publishedYes

    Research areas

  • Chromosome Aberrations, Chromosome Mapping, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogenes, Sequence Deletion, Transcriptional Activation, Translocation, Genetic, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

See relations at Aarhus University Citationformats

ID: 116723492