Penn study on silencing of Tumor Suppressor Gene sets new goal for Lymphoma

Mariusz a. Wasik, MD, professor of pathology and laboratory medicine and Qian Zhang, MD, PhD, research assistant professor, both of the Perelman School of Medicine at the University of Pennsylvania, and their colleagues, found that a cancer-causing fusion protein works by silencing of tumor suppressor genes IL-2R common gamma chain (IL-2R?). The results, which in a recent work of the National Academy of Sciences, suggest News targets for lymphoma and other cancers.

Fusion proteins are created by two genes--originally coding for separate proteins--to merge. Translation of the fusion gene in an active proteins results in a molecule with properties derived from each of the originals. Fusion proteins relatively commonly found in cancer cells.

The team looked a fusion protein NPM-ALK. Anaplastic Lymphoma kinase (ALK), which is expressed only physiologically by neurons in fetal life, causes cancer, when it wrongly is expressed in non-nerve tissue as a fusion protein with nucleophosphin (NPM) and other partners. NPM-ALK works by silencing of tumor suppressor genes IL-2R?. The ALK fusion genes are active in different types of cancer including some carcinomas of the lung, kidney and thyroid.

The protein IL-2R? is shared by receptors for several proteins called cytokines that play an important role in the maturation and growth of normal immune cells called CD4 + T-cells play. The team of Penn found that IL-2R? expression in T-cell lymphoma cells NPM-ALK express due to epigenetic silencing is inhibited. The IL-2R? gene promoter is silenced by a chemical change to the DNA itself, in this case, adding a methyl group to DNA Molecular backbone.

Role epigenetic silencing

Epigenetic gene silencing represents an important mechanism for the inhibition of the tumor suppressor gene expression in cancer cells. The silencing affects gene promoter regions within DNA, in two ways: DNA methylation, or the modification of replace histones and other proteins. The methylation is mediated by enzymes called DNA methyl transfer ases (DNMTs). Replace histones can be changed by Histone deacetylases.

Silence of the promoter of the IL-2R? via methylation is induced in malignant t cells by NPM-ALK by activating another called STAT3. STAT3 increases the expression of one of the DNMTs and facilitates the attachment of this and other DNMTs to the IL-2R? gene Organizer. Striking, as IL-2R? is expressed, NPM-ALK disappears from the cancer cells of T, and they eventually die. These results show that NPM-ALK induces epigenetic silencing of the IL-2R? gene and that IL-2R? acts as a tumor suppressor by reciprocally inhibition of expression of NPM-ALK.

"Epigenetic silencing is not an independent event, and genetics-in the form of the aberrant fusion protein-drives an epigenetic change," said Wasik. "Is this generalizable phenomenon? We can overcome the tumor suppressor genes silencing with inhibitors of DNA methylation, that are already approved for the treatment of some forms of cancer of the blood, to inhibit the expression of NPM-ALK and possibly other carcinogenic proteins in patients? "

This approach can potentially complementary and inhibition of fusion protein activity such as routine for BCR-ABL in chronic myelogeneous leukemia and experimental for ALK in lung carcinoma, lymphoma and other malignancies express ALK is done.

The research was funded by grants from the National Cancer Institute and the leukemia and Lymphoma Society.

Article reference:
University of Pennsylvania School of Medicine