Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New mutations in leukemia: Researchers found mechanism that can help design future therapies

05.09.2011
Results will be published next Sunday in Nature Genetics

An international team of researchers has found a group of mutations involved in T-cell acute lymphoblastic leukemia (T-ALL), and showed that certain drugs, already in clinical use to treat other diseases, can eliminate the cells carrying these mutations.

Results* will be published next week in Nature Genetics and may promote the development of novel therapeutic approaches against leukemia.

The study was led by researcher João T. Barata at Instituto de Medicina Molecular in Lisbon, Portugal, jointly with J. Andres Yunes at Centro Infantil Boldrini in Campinas, São Paulo, Brazil, in collaboration with researchers from the National Cancer Institute in Frederick, Maryland, USA, the Erasmus Medical Center, Rotterdam, The Netherlands; and other laboratories in Europe and the US.

This is a basic research study with potential clinical impact, which was performed, in part, using samples from pediatric leukemia patients.

T-ALL affects mostly children. It is a blood cancer consisting in an uncontrolled growth in the number of T-lymphocytes (white blood cells from the immune system).

The onset of the disease can be triggered by different genetic mutations in genes involved in the proliferation and differentiation of T-cells.

The identification and study of mutations found in leukemia patients is particularly important to help develop more efficient and targeted therapies. Researchers now found a group of mutations that affect 9% of the patients with T-ALL and that may originate leukemia in these patients.

Most importantly, researchers demonstrated that a set of pharmaceutical drugs can eliminate the effect of these mutations, unraveling a potential therapeutic application for their discovery.

The current study shows that the mutations occur at the gene coding for a protein localized at the surface of T-cells, the interleukin-7 receptor (IL7R).

This protein contacts with both the exterior and the interior of the cells, acting as a bridge to transfer chemical information from the outside to the inside of cells. Information transfer occurs upon the binding of a bloodstream protein (interleukin-7) to the receptor, which triggers a cascade of cellular reactions that are essential for the correct development and proliferation of T-cells.

In the new study, researchers also found that the mutations promote non-stop, uncontrolled T-cell proliferation, independently of extracellular triggers. This capacity to induce cells to grow relentlessly is associated with the ability to originate tumors.

To help fighting the tumors that contain IL7R mutations, the team of researchers studied pharmaceutical drugs known to act in several steps of the referred cascade of cellular reactions and found that these drugs - which are already being tested against other diseases such as rheumatoid arthritis – can stop cell proliferation induced in mutated cells and promote the elimination of these cells.

Says João T. Barata: "We discovered that the interleukin-7 receptor, which is essential for proper T-cell development, may also have a "dark side", acting as a Mr. Hyde of sorts. In particular, we found that certain mutations in this gene are involved in pediatric T-cell acute lymphoblastic leukemia and characterized how they act. Our observations allowed us to identify potential therapeutic weapons against these tumors. Although pediatric acute lymphoblastic leukemia is among the success stories in cancer therapy, improvements are still needed. We hope our findings will help further increase the efficacy and selectivity of already existing treatments."

Says J. Andrés Yunes, from Centro Infantil Boldrini in Campinas, São Paulo, Brazil: "Most mutations found resulted in the insertion of a cystein aminoacid into the IL7R. It is this new cystein that perverts the normal functioning of the receptor by linking two mutant IL7R molecules through disulfide bonds. I'm eager to know what is the probability of having a cystein codon insertion, in this specific location of the gene, to address whether this is random or not."

Says Scott K. Durum, from the National Cancer Institute in Frederick, Maryland, USA: "On the one hand, the IL-7 receptor should have seemed a likely cause of cancer because it normally stimulates cells to grow, which is what cancer cells do. On the other hand this seemed unlikely because there are normally two chains involved in signaling. However these remarkable mutations in just one of the chains circumvent the need for the second chain. In addition to existing drugs that can target this pathway, we aim to develop new antibodies against IL-7 receptor to treat these patients. "

This research was funded by several funding agencies, in particular by the Portuguese Foundation for Science and Technology (FCT - Fundação Portuguesa para a Ciência e a Tecnologia), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and the intramural program of the National Cancer Institute, NIH.

* Title: "Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia", authors: Priscila P. Zenatti, Daniel Ribeiro, Wenqing Li, Linda Zuurbier, Milene C. Silva, Maddalena Paganin, Julia Tritapoe, Julie A. Hixon, André B. Silveira, Bruno A. Cardoso, Leonor M. Sarmento, Nádia Correia, Maria L. Toribio, Jörg Kobarg, Martin Horstmann, Rob Pieters, Silvia R. Brandalise, Adolfo A. Ferrando, Jules P. Meijerink, Scott K. Durum, J. Andrés Yunes and João T. Barata

Marta Agostinho | EurekAlert!
Further information:
http://www.fm.ul.pt

More articles from Health and Medicine:

nachricht Organ-on-a-chip mimics heart's biomechanical properties
23.02.2017 | Vanderbilt University

nachricht Researchers identify cause of hereditary skeletal muscle disorder
22.02.2017 | Klinikum der Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>