Le gène Dlx5

Mise à jour, l'article date de avril 2015

Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphoma (T-ALL), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in T-ALL. We previously demonstrated that transgenic expression of a constitutively active form of Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of c-Myc or Dlx5 caused by specific chromosomal rearrangements. Here we report that transgenic overexpression of Dlx5 specifically in the mouse thymus can also drive T-cell lymphomagenesis. Tumors from these mice were characterized by loss of Pten expression and trisomy 15. Proliferation of these lymphoma cells was highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001 as well as to the Myc inhibitor JQ1. Additionally, BEZ235 was found to cooperate with JQ1 to induce a more profound effect on cell cycle arrest and apoptosis. Moreover, BEZ235 potentiated vincristine-induced apoptosis when cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. These findings suggest that combination therapies with AKT and MYC inhibitors hold promise for the treatment of T-ALL in the clinic.


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L'activation constitutive de AKT est un phénomène fréquent dans le développement de cellules T humaines de la leucémie lymphocytique aiguë / lymphome (T-ALL), principalement en raison de l'inactivation de PTEN. La régulation de MYC est aussi communément observé dans T-ALL. Nous avons précédemment démontré que l'expression transgénique d'une forme constitutivement active de Akt2 seule est suffisante pour amorcer le lymphome à cellules T chez la souris, et que la formation de tumeur nécessite typiquement jusqu'à la régulation de c-Myc ou Dlx5 provoquée par des réarrangements chromosomiques spécifiques. Nous rapportons ici que la surexpression transgénique de Dlx5 spécifiquement dans le thymus de la souris peut également conduire la lymphomagenèse de la cellule T. Les tumeurs provenant de ces souris ont été caractérisées par la perte de PTEN et la trisomie 15. La prolifération de ces cellules de lymphome est très sensible aux inhibiteurs de Akt BEZ235 et RAD001 ainsi qu'à l'inhibiteur de Myc JQ1. En outre, BEZ235 s'est trouvé à coopérer avec JQ1 pour induire un effet plus profond sur l'arrestation et l'apoptose du cycle cellulaire. Par ailleurs, l'apoptose induite par BEZ235 a potentialisé le vincristine, lorsque les cellules ont été traitées avec les deux médicaments simultanément, alors que le prétraitement avec BEZ235 antagonise l'effet tuant les cellules de la vincristine. Ces résultats suggèrent que les thérapies de combinaison avec des inhibiteurs de AKT et MYC sont prometteuses pour le traitement de la LAL-T dans la clinique.

(Feb. 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.

Un gène crucial pour le développement de l'embryon peut rapidement devenir un puissant promoteur du cancer chez la souris adulte après une erreur de séquensage selon les chercheurs. Erreur qui cause la cancérisation spontanée des cellules blanches. Dans le numéro du premier Mars de Cancer Research les chercheurs expliquent en détail comment le gène appelé Dlx5 travaille en coopération avec l'oncogène Akt2 pour amener le cancer chez les souris. La protéine qu'encode Dlx5 pourrait être une cible pour les médicaments qui réduiraient la croissance des lymphomes et de d'autres cancers chez l'humain.


"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 in the majority of mice studied. One particular line of transgenic mice exhibited the inversion in 15 of 15 tumors they examined. "Genetic recombination is a frequent component of T-cell malignancies, but it is startling to see this same pattern come up repeatedly," Testa says.

In subsequent cell studies, Testa and his colleagues determined that the combined activation of both Dlx5 and Akt2 could result in increased cell growth and proliferation. While their findings are the first to assert that Dlx5 can be an oncogene, the gene has previously been implicated in a number of human endometrial and lung cancers. Moreover, the DLX5 protein was found in abundant amounts within three out of seven human lymphomas that the Fox Chase researchers examined.

According to Testa, molecules that could bind and inhibit DLX5 could provide a more useful drug for therapeutic development than could molecules that inactivate AKT2.

"The AKT family of proteins is crucial to survival in both cancerous and non-cancerous cells, so AKT2 is a potentially risky target for drug development since blocking AKT2 can also kill healthy cells," Testa says. "DLX5, however, is not generally active in healthy adult cells, so it represents a much more 'druggable' target for inhibition."