Institut for Biomedicin

Rasmus Bak

Activation of proto-oncogenes by disruption of chromosome neighborhoods

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DOI

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

OriginalsprogEngelsk
TidsskriftScience
Vol/bind351
Nummer6280
Sider (fra-til)1454-1458
Antal sider5
ISSN0036-8075
DOI
StatusUdgivet - 25 mar. 2016
Eksternt udgivetJa

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