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Activation of proto-oncogenes by disruption of chromosome neighborhoods

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

DOI

  • Denes Hnisz, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
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  • Abraham S Weintraub, Massachusetts Institute of Technology
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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, Massachusetts Institute of Technology
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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, Massachusetts Institute of Technology
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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, Massachusetts Institute of Technology
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  • Diego Borges-Rivera, Massachusetts Institute of Technology
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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, Massachusetts Institute of Technology
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  • Matthew H Porteus, Stanford University
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  • Job Dekker, Howard Hughes Medical Institute
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  • Richard A Young, Massachusetts Institute of Technology

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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