Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Penn Study on Silencing of Tumor Suppressor Gene Suggests New Target for Lymphoma

10.08.2011
Mariusz A. Wasik, MD, professor of Pathology and Laboratory Medicine, and Qian Zhang, MD, PhD, research assistant professor, both from the Perelman School of Medicine at the University of Pennsylvania, and their colleagues, found that a cancer-causing fusion protein works by silencing the tumor suppressor gene IL-2R common gamma-chain (IL-2Rã). The results, which appeared in a recent Proceedings of the National Academy of Sciences, suggest news targets for lymphoma and other types of cancer.

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

The team looked at a fusion protein called NPM-ALK. Anaplastic lymphoma kinase (ALK), which physiologically is expressed only by neurons in fetal life, causes cancer when it is mistakenly expressed in non-neural tissues as a fusion protein with nucleophosphin (NPM) and other partners. NPM-ALK works by silencing the tumor suppressor gene IL-2Rã. The ALK fusion genes are active in several cancer types including some carcinomas of the lung, thyroid, and kidney.

The protein IL-2Rã is shared by receptors for several proteins called cytokines that play key roles in the maturation and growth of normal immune cells called CD4+ T cells. The Penn team found that IL-2Rã expression is inhibited in T-cell lymphoma cells expressing NPM-ALK as a result of epigenetic silencing. The IL-2Rã gene promoter is silenced by a chemical change to the DNA itself, in this case, the adding of a methyl group to DNA's molecular backbone.

Role of Epigenetic Silencing
Epigenetic gene silencing represents an important mechanism of inhibiting tumor suppressor gene expression in cancer cells. The silencing affects gene promoter regions within DNA, in two ways: methylation of the DNA and modification of histones and other proteins. The methylation is mediated by enzymes called DNA methyltransferases (DNMTs). Histones are modified by histone deacetylases.

Silencing of the IL-2Rã promoter via methylation is induced in malignant T cells by NPM-ALK by activating another protein called STAT3. STAT3 increases expression of one of the DNMTs and facilitates attachment of this and other DNMTs to the IL-2Rã gene promoter. Strikingly, when IL-2Rã is expressed, NPM-ALK disappears from the cancerous T cells, and they eventually die. These results demonstrate that NPM-ALK induces epigenetic silencing of the IL-2Rã gene and that IL-2Rã acts as a tumor suppressor by reciprocally inhibiting 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," says Wasik. "Is this phenomenon generalizable? Can we overcome the tumor suppressor gene silencing using inhibitors of DNA methylation, which are already approved to treat some forms of blood cancer, to inhibit the expression of NPM-ALK and possibly other cancer-causing proteins in patients?"

This approach could potentially complement inhibition of fusion protein activity as is routinely done for BCR-ABL in chronic myelogeneous leukemia and experimentally for ALK in lung carcinoma, lymphoma and other malignancies expressing ALK.

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

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Oestrogen regulates pathological changes of bones via bone lining cells
28.07.2017 | Veterinärmedizinische Universität Wien

nachricht Programming cells with computer-like logic
27.07.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Abrupt motion sharpens x-ray pulses

Spectrally narrow x-ray pulses may be “sharpened” by purely mechanical means. This sounds surprisingly, but a team of theoretical and experimental physicists developed and realized such a method. It is based on fast motions, precisely synchronized with the pulses, of a target interacting with the x-ray light. Thereby, photons are redistributed within the x-ray pulse to the desired spectral region.

A team of theoretical physicists from the MPI for Nuclear Physics (MPIK) in Heidelberg has developed a novel method to intensify the spectrally broad x-ray...

Im Focus: Physicists Design Ultrafocused Pulses

Physicists working with researcher Oriol Romero-Isart devised a new simple scheme to theoretically generate arbitrarily short and focused electromagnetic fields. This new tool could be used for precise sensing and in microscopy.

Microwaves, heat radiation, light and X-radiation are examples for electromagnetic waves. Many applications require to focus the electromagnetic fields to...

Im Focus: Carbon Nanotubes Turn Electrical Current into Light-emitting Quasi-particles

Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers

Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...

Im Focus: Flexible proximity sensor creates smart surfaces

Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.

At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...

Im Focus: 3-D scanning with water

3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects

A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

 
Latest News

New 3-D imaging reveals how human cell nucleus organizes DNA and chromatin of its genome

28.07.2017 | Health and Medicine

Heavy metals in water meet their match

28.07.2017 | Power and Electrical Engineering

Oestrogen regulates pathological changes of bones via bone lining cells

28.07.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>