期刊
SCIENCE
卷 351, 期 6280, 页码 1454-1458出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad9024
关键词
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资金
- NIH [HG002668, CA109901, NS088538, MH104610, AI120766, U54 DK107980, U01 DA 040588]
- Austrian Science Fund (FWF) [J3490]
- Ludwig Graduate Fellowship funds
- Laurie Kraus Lacob Faculty Scholar Award in Pediatric Translational Research
- Hyundai Hope on Wheels
- Danish Council for Independent Research, Medical Sciences [DFF-1333-00106B, DFF-1331-00735B]
- National Human Genome Research Institute [R01 HG003143, U54 HG007010, U01 HG007910]
- National Cancer Institute [U54 CA193419]
- National Institute of General Medical Sciences [R01 GM 112720]
- National Institute of Allergy and Infectious Diseases [U01 R01 AI 117839]
- Austrian Science Fund (FWF) [J 3490] Funding Source: researchfish
- Austrian Science Fund (FWF) [J3490] Funding Source: Austrian Science Fund (FWF)
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 Tcell 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.
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