Chromosomal Translocations: Chicken or Egg?

Inappropriate upregulation of genes on chromosomes 2 and 5 (stained pink and green) in anaplastic large cell lymphoma  leads to reorganization of surrounding DNA and its regulatory proteins, resulting in the spatial convergence of these two chromosomes within the nucleus.

Inappropriate upregulation of genes on chromosomes 2 and 5 (stained pink and green) in anaplastic large cell lymphoma leads to reorganization of surrounding DNA and its regulatory proteins, resulting in the spatial convergence of these two chromosomes within the nucleus.

Many tumor cells have abnormal chromosomes. Some of these abnormalities are caused by chromosomal translocations, which occur when two chromosomes break and incorrectly rejoin, resulting in an exchange of genetic material. Translocations can activate oncogenes, silence tumor suppressor genes, or result in the creation of completely new fusion gene products. While there is little doubt that chromosomal translocations can contribute to cancer, there is an active "chicken and the egg" discussion about the role translocations and other chromosomal abnormalities play—do they actually cause cancer or merely occur because of other changes within the cancer cell.

 

The majority of anaplastic large cell lymphomas (ALCLs) exhibit a characteristic chromosomal translocation referred to as t(2;5)(p23;q35), or t(2;5) for short. The exchange of genetic material between chromosomes 2 and 5 results in the creation of a fusion protein called NPM-ALK. It seems reasonable to assert that NPM-ALK plays a role in ALCL: the fusion protein can cause malignancies in animal models. However, there is a subset of ALCLs that do not have t(2;5) or NPM-ALK, raising the possibility that this cancer is initiated by other factors.

Tom Misteli, Ph.D., Head of the CCR Cell Biology of Genomes Group, and Karen Meaburn, Ph.D., a visiting postdoctoral fellow in his lab, teamed up with a research group in Germany to learn more about the molecular events that drive ALCL and the mechanism of chromosomal translocation in this disease. The provocative results of their work are described in a recent paper in the Proceedings of the National Academy of Sciences.

The team looked at eight ALCL cell lines—four with and four without the characteristic translocation. Interestingly, both types of cell lines exhibited deregulation of several genes located within the regions of chromosomes 2 and 5 that tend to undergo translocation. The products of these genes—Id2, Fra2, and CSF1-receptor—promote cell survival and repress differentiation, and experiments in cell culture suggest that they may play an important role in ALCL biology regardless of whether the t(2;5) translocation is present.

The researchers made another fascinating observation—in t(2;5)-negative ALCL cells that exhibited gene deregulation, chromosomes 2 and 5 were located very close to one another (this was not the case in non-ALCL cells). It was speculated that this spatial relationship might predispose the ALCL cells to the t(2;5) translocation, a notion supported by the fact that treating these cells with ionizing radiation (which induces double-strand DNA breaks) resulted in the formation of this characteristic chromosomal abnormality.

Together, these results suggest that the t(2;5) chromosomal translocation may not be the first step in the transformation of normal T cells to cancerous ALCL cells. The authors assert that the inappropriate upregulation of genes on chromosomes 2 and 5 leads to reorganization of surrounding DNA and its regulatory proteins, resulting in the spatial convergence of these two chromosomes within the nucleus. This close association predisposes the cell to the t(2;5) translocation. Although t(2;5) is common in ALCL and may contribute to its growth, this updated paradigm suggests that deregulation of key genes is an earlier event in the development of ALCL and perhaps other cancer as well.

Summary Posted: Wed, 04/01/2009

Reference

Proc Natl Acad Sci. 2009 Apr 7;106(14):5831-6. Epub 2009 Mar 25 PubMed Link