Activation of Proto-oncogenes by Disruption of Chromosome Neighborhoods

Overview

Journal Science

Specialty Science

Date 2016 Mar 5

PMID 26940867

Citations 561

Authors

Denes Hnisz

Abraham S Weintraub

Daniel S Day

Anne-Laure Valton

Rasmus O Bak

Charles H Li

Johanna Goldmann

Bryan R Lajoie

Zi Peng Fan

Alla A Sigova

Jessica Reddy

Diego Borges-Rivera

Tong Ihn Lee

Rudolf Jaenisch

Matthew H Porteus

Job Dekker

Richard A Young

Affiliations

Soon will be listed here.

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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