Publication Date:
2016-03-05
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hnisz, Denes -- Weintraub, Abraham S -- Day, Daniel S -- Valton, Anne-Laure -- Bak, Rasmus O -- Li, Charles H -- Goldmann, Johanna -- Lajoie, Bryan R -- Fan, Zi Peng -- Sigova, Alla A -- Reddy, Jessica -- Borges-Rivera, Diego -- Lee, Tong Ihn -- Jaenisch, Rudolf -- Porteus, Matthew H -- Dekker, Job -- Young, Richard A -- AI120766/AI/NIAID NIH HHS/ -- CA109901/CA/NCI NIH HHS/ -- HG002668/HG/NHGRI NIH HHS/ -- MH104610/MH/NIMH NIH HHS/ -- NS088538/NS/NINDS NIH HHS/ -- R01 GM 112720/GM/NIGMS NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- R01 MH104610/MH/NIMH NIH HHS/ -- U01 DA 040588/DA/NIDA NIH HHS/ -- U01 HG007910/HG/NHGRI NIH HHS/ -- U01 R01 AI 117839/AI/NIAID NIH HHS/ -- U54 CA193419/CA/NCI NIH HHS/ -- U54 DK107980/DK/NIDDK NIH HHS/ -- U54 HG007010/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1454-8. doi: 10.1126/science.aad9024. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. ; Department of Pediatrics, Stanford University, Stanford, CA, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Howard Hughes Medical Institute. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. young@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940867" target="_blank"〉PubMed〈/a〉
Keywords:
*Chromosome Aberrations
;
Chromosome Mapping
;
*Gene Expression Regulation, Leukemic
;
HEK293 Cells
;
Humans
;
Mutation
;
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics
;
Proto-Oncogenes/*genetics
;
*Sequence Deletion
;
Transcriptional Activation
;
*Translocation, Genetic
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
