Activation of proto-oncogenes by disruption of chromosome neighborhoods
Related Experiment Video
Updated: Mar 24, 2026
HOX Loci Focused CRISPR/sgRNA Library Screening Identifying Critical CTCF Boundaries
Published on: March 31, 2019
Denes Hnisz1, Abraham S Weintraub1,2, Daniel S Day1
1Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
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.
Insights
Proto-oncogenes can become oncogenes through disruptions in insulated neighborhoods, crucial chromosome structures. Genetic alterations breaking these boundaries activate oncogenes, driving cancer development.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Oncogene activation typically results from gene fusion, translocation, or amplification.
- Insulated neighborhoods are chromosomal structures that regulate key gene expression.
- The role of insulated neighborhoods in oncogene activation is not well understood.
Purpose of the Study:
- To investigate if proto-oncogenes reside within insulated neighborhoods.
- To determine if disruption of insulated neighborhood boundaries can activate oncogenes.
- To explore the role of insulated neighborhood disruption in cancer development.
Main Methods:
- Mapping of insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) genomes.
- Analysis of tumor cell genomes for microdeletions affecting boundary sites.
- Experimental perturbation of boundary sites in nonmalignant cells.
Main Results:
- Recurrent microdeletions were identified at boundary sites of insulated neighborhoods containing T-ALL proto-oncogenes.
- Disruption of these boundaries in nonmalignant cells led to proto-oncogene activation.
- Mutations impacting chromosome neighborhood boundaries are prevalent across various cancer types.
Conclusions:
- Oncogene activation can occur through genetic alterations that disrupt insulated neighborhoods.
- Insulated neighborhoods represent a novel mechanism in oncogene activation and cancer development.
- Targeting insulated neighborhood integrity may offer new therapeutic strategies for cancer.
More Related Videos
10:09Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
09:40Quantitation and Analysis of the Formation of HO-Endonuclease Stimulated Chromosomal Translocations by Single-Strand Annealing in Saccharomyces cerevisiae
Published on: September 23, 2011
Related Concept Videos
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:33Cancer-Critical Genes I: Proto-oncogenes
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions