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Activation of proto-oncogenes by disruption of chromosome neighborhoods

Science  25 Mar 2016:
Vol. 351, Issue 6280, pp. 1454-1458
DOI: 10.1126/science.aad9024

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The spread of bad neighborhoods

Our genomes have complex three-dimensional (3D) arrangements that partition and regulate gene expression. Cancer cells frequently have their genomes grossly rearranged, disturbing this intricate 3D organization. Hnisz et al. show that the disruption of these 3D neighborhoods can bring oncogenes under the control of regulatory elements normally kept separate from them (see the Perspective by Wala and Beroukim). These novel juxtapositions can result in the inappropriate activation of oncogenes.

Science, this issue p. 1454; see also p. 1398

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.

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