A recent scientific discovery made by researchers at the Institut de recherches cliniques de Montréal (IRCM) led by Dr. Javier Marcelo Di Noia, Director of the Mechanisms and Genetic Diversity research unit, was published online today by The Journal of Experimental Medicine.
The team identified a mechanism regulating activation-induced deaminase (AID), which could be important for the therapy of some types of lymphoma and leukemia.
AID is a B-lymphocyte enzyme that creates deliberate mutations in the DNA encoding antibodies, which helps produce an appropriate immune response. However, inappropriate expression of AID can also have harmful effects and lead to certain oncogenic (cancer-causing) mutations. When found in a tumour, uncontrolled levels of AID could increase the rate of gene mutation and, in turn, accelerate the progression of the disease.
"In studying the regulation of AID, we attempted to understand what restricts its access to the cell's nucleus," explains Alexandre Orthwein, doctoral student in Dr. Di Noia's research unit and first author of this study. "If we could control that aspect, we could prevent AID's negative mutating effects. We then discovered that Hsp90, one of the most abundant and vital proteins found in cells, stabilizes AID in the cytoplasm. Cytoplasmic AID is in fact in a dynamic equilibrium regulated by Hsp90."
By stabilizing AID, Hsp90 determines the enzyme's overall expression levels, which correlate with the extent of its physiological functions. Hence, Hsp90 assists AID-mediated antibody diversification. A number of Hsp90 inhibitors being commercially available, the researchers found that Hsp90 inhibition destabilizes AID, thus resulting in a proportional reduction in antibody gene diversification. Moreover, since AID levels also correlate with its pathological side effects, Hsp90 inhibition prevents uncontrolled off-target mutation by AID.
"We showed that inhibiting Hsp90 with known drugs, which are also currently used in clinical trials for the treatment of certain cancers, significantly reduces the amount of AID and, consequently, prevents this enzyme's undesired activity on DNA," adds Dr. Di Noia. "This regulatory mechanism determines the functional levels of AID in normal B cells and B cell lymphoma lines. So, Hsp90 inhibition provides the first pharmacological means to regulate AID expression and activity, which could be relevant for the therapy of some types of lymphoma and leukemia."
Dr. Di Noia, along with the IRCM's Technology Transfer Office, is currently taking the necessary steps to patent the proposed application of the Hsp90 inhibitors with the Canadian Intellectual Property Office (CIPO) and the United States Patent and Trademark Office (USPTO). These patent applications, promoted and commercialized by Univalor, cover the use of the AID biomarker in the selection of a cancer-fighting therapy. In the context of this technology, the treatment using an Hsp90 inhibitor targets tumours expressing AID, and consists of the administration of predetermined doses of the inhibitor in accordance with the expression levels of AID in the tumours.
According to The Leukemia & Lymphoma Society of Canada, one person is diagnosed with a blood cancer every four minutes and someone dies from a blood cancer every 10 minutes. This statistic represents over 54,000 people per year. In 2010, about 628,415 people are living with lymphoma or are in remission.
This research project was supported by the Canadian Institutes of Health Research (CIHR). "CIHR is proud to support the type of innovative research that Dr. Javier Marcelo Di Noia and his team are engaging in," says Dr. Morag Park, Scientific Director for CIHR's Institute of Cancer Research. "An understanding of the mechanisms that regulate activation-induced deaminase by heat shock protein 90 (Hsp90) will provide potential new therapies to treat some types of leukemia and lymphoma." The project also received support from the Cancer Research Society (CRS) and the Canada Research Chair program. In addition, Alexandre Orthwein holds a Cole Foundation doctoral fellowship.
Other researchers contributed to the study, including Anne-Marie Patenaude, research assistant in Dr. Di Noia's laboratory, El Bachir Affar from the Hôpital Maisonneuve-Rosemont, Alain Lamarre from the INRS-Institut Armand-Frappier research centre, and Jason C. Young from McGill University.
For more information, please refer to the online article summary published by The Journal of Experimental Medicine. The print publication will be available on November 22, 2010
Julie Langelier | EurekAlert!
Matabele ants: Travelling faster with detours
21.05.2018 | Julius-Maximilians-Universität Würzburg
Asian tiger mosquito on the move
20.05.2018 | Goethe-Universität Frankfurt am Main
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...
A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.
The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...
Cardiovascular tissue engineering aims to treat heart disease with prostheses that grow and regenerate. Now, researchers from the University of Zurich, the Technical University Eindhoven and the Charité Berlin have successfully implanted regenerative heart valves, designed with the aid of computer simulations, into sheep for the first time.
Producing living tissue or organs based on human cells is one of the main research fields in regenerative medicine. Tissue engineering, which involves growing...
A team of scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg investigated optically-induced superconductivity in the alkali-doped fulleride K3C60under high external pressures. This study allowed, on one hand, to uniquely assess the nature of the transient state as a superconducting phase. In addition, it unveiled the possibility to induce superconductivity in K3C60 at temperatures far above the -170 degrees Celsius hypothesized previously, and rather all the way to room temperature. The paper by Cantaluppi et al has been published in Nature Physics.
Unlike ordinary metals, superconductors have the unique capability of transporting electrical currents without any loss. Nowadays, their technological...
02.05.2018 | Event News
13.04.2018 | Event News
12.04.2018 | Event News
18.05.2018 | Power and Electrical Engineering
18.05.2018 | Information Technology
18.05.2018 | Information Technology