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Inverted DNA turns quiet developmental gene into a potent driver of t-cell lymphoma
Date:2/27/2008

A gene crucial for embryonic development can quickly become a potent cancer promoter in adult mice after a genetic misalignment, according to researchers from Fox Chase Cancer Center, causing white blood cells to become cancerous spontaneously.

In the March 1 issue of the journal Cancer Research, the researchers detail how a gene called Dlx5 works cooperatively with a known oncogene, Akt2, to drive cancer in mice. The protein that Dlx5 encodes could be a target for drugs to slow the growth of lymphomas and other cancers in humans, they say.

A chromosomal inversion essentially flips a segment of DNA, placing the Dlx5 gene next to an enhancer in a neighboring gene, which in turn activates a number of other nearby genes, says lead investigator Joseph Testa, Ph.D., a cancer geneticist at Fox Chase. The result is like placing a V8 engine on a Flexible Flyer something is going to go fast and without much control.

According to Testa, Dlx5 is basically a good gene that starts to do bad things when it moves into a dangerous neighborhood. Dxl5 is part of the homeobox family of genes, which direct the timing of events in the physical development of a growing fetus, such as when to sprout a limb, for example. In adults, such genes are almost entirely inactive.

Unfortunately, in white blood cells, such as T cells, Dlx5 moves to a region of DNA involved in the genetic rearrangement that allows immune cells to switch genes around in order to create new combinations of proteins to respond to disease threats. This recombination process allows B cells to generate antibodies and T cells to generate T cell receptors, enabling the immune system to recognize an enormous array of foreign bacteria, viruses and parasites.

In a mouse model of T cell lymphoma, the researchers found that mice bred to over-express the Akt2 gene also over-expressed Dlx5. In fact, the researchers found the chromosomal inversion that led to cancer was a feature
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Contact: Greg Lester
gregory.lester@fccc.edu
215-728-2753
Fox Chase Cancer Center
Source:Eurekalert

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