title: Activation of proto-oncogenes by disruption of chromosome neighborhoods.
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.
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Denes
authors.initials: D
authors.lastname: Hnisz
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Abraham S
authors.initials: AS
authors.lastname: Weintraub
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Day
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Valton
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors.forename: Rasmus O
authors.initials: RO
authors.lastname: Bak
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Li
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Goldmann
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Lajoie
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Zi Peng
authors.initials: ZP
authors.lastname: Fan
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Alla A
authors.initials: AA
authors.lastname: Sigova
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Reddy
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Borges-Rivera
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Tong Ihn
authors.initials: TI
authors.lastname: Lee
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Porteus
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605-0103, USA.|Howard Hughes Medical Institute.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
mesh_terms: D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D017384:Sequence Deletion; D015533:Transcriptional Activation; D014178:Translocation, Genetic