Findings published in Cancer Research showed that a mouse model bred to overexpress Akt2 also overexpressed Dlx5, and together could increase cell growth and proliferation.
Fox Chase Cancer Center investigators found that a gene crucial for embryonic development, Dxl5, can become a cancer promoter in adult mice. This occurs after a genetic misalignment which causes white blood cells to become cancerous spontaneously.
Dxl5 is part of the homeobox family of genes, which direct the timing of events in the physical development of a growing fetus. In adults, such genes are almost entirely inactive.
In a mouse model of T-cell lymphoma, the researchers found that mice bred to overexpress the Akt2 gene also overexpressed Dlx5. They discovered that a chromosomal inversion in white blood cells moves Dlx5 to a region of DNA involved in the genetic rearrangement that allows immune cells to switch genes around to create new combinations of proteins to respond to disease threats, which in turn activates a number of other nearby genes.
This chromosomal inversion was a feature in the majority of mice studied, report the scientists. One particular line of transgenic mice exhibited the inversion in all 15 tumors they examined.
In subsequent cell studies, the team determined that the combined activation of both Dlx5 and Akt2 could result in increased cell growth and proliferation. Moreover, the Dlx5 protein was found in abundant amounts within three out of seven human lymphomas that the Fox Chase researchers examined.
“The AKT family of proteins is crucial to survival in both cancerous and noncancerous cells, so AKT2 is a potentially risky target for drug development since blocking AKT2 can also kill healthy cells,” explains lead investigator, Joseph Testa, Ph.D., a cancer geneticist at Fox Chase. “DLX5, however, is not generally active in healthy adult cells, so it represents a much more druggable target for inhibition.”
The study will be published in the March 1 issue of Cancer Research.
