ScienceDaily (Dec. 7, 2010) — Using a new technology called “differential epistasis maps,” an international team of scientists, led by researchers at the University of California, San Diego School of Medicine, has documented for the first time how a cellular genetic network completely rewires itself in response to stress by DNA-damaging agents.

The research — to be published in the December 3 issue of Science — is significant because it represents a major technological leap forward from simply compiling lists of genes in an organism to actually describing how these genes actively work together.

“Cell behavior is dynamic, but the genetic networks that govern these behaviors have been studied mostly only under normal, benign laboratory conditions,” said Trey Ideker, PhD, professor of medicine and bioengineering, and chief of the Division of Medical Genetics in the UCSD School of Medicine. “This work is the next milestone. It shows that we can map how genetic networks in cells are reprogrammed in response to stimuli, thus revealing functional relationships that would go undetected using other approaches.”

Think of it as the difference in the informational value of a photograph versus a video. In the photo, details and data are restricted to what’s contained in a single, captured moment. There’s no way to determine exactly what occurred before or after, or how players in the picture changed. In a video, on the other hand, whole sequences of events- dynamic processes and responses, interactions and relationships — can be chronicled, identified and studied.

“This study is the first of its kind,” said co-author Nevan Krogan, an associate professor of cellular and molecular pharmacology at UC San Francisco. Ideker, who is also principal investigator of the new National Resource for Network Biology, based at UC San Diego, called it “paradigm-shifting.”

Epistasis refers to the interaction of genes and how they suppress, amplify or alter each other’s functions. To create a differential epistasis map, the researchers focused on 400 or so genes that govern the signaling pathways in a yeast cell. They then created 80,000 double-mutant cell lines in which each line carried mutations in a different pair of the 400 genes. When double-mutant cells grow much more slowly or quickly than expected, these mutant genes are said to interact.

To create the differential map, interactions were identified both before and after exposure to a DNA-damaging compound similar to drugs used in chemotherapy. These two networks were then subtracted, one from the other, to reveal differences. Remarkably, researchers found that most of the interactions identified with the drug were not present without it, and vice versa. In other words, the genetic network was completely reprogrammed by DNA damage.

As researchers progress in mapping these networks, their dynamic nature is both enlightening and depressing, said Ideker. Scientists had hoped cellular networks might not change greatly across different conditions or from cell to cell. That they do so suggests greater challenges and complexities ahead.

“As we look to extend this approach to mammalian systems and ultimately to human cells, new challenges will arise — the ability to selectively control the genetic makeup of cells, the redundancy in genes, transcription factors and other molecules that make more advanced systems more robust, but also more complicated to study,” said David Balshaw, program officer for the National Institute of Environmental Health Sciences, which funded the study.

Ideker agreed that there is a lot more work to do. “The Human Genome Project has identified 30,000 genes and their sequence variants across different individuals. However, it leaves completely unanswered how these different genes interact to form the molecular machines that run the cell and govern its various responses. We now have the parts list, but we also need to understand the network connecting all of these parts, and how to fix it during disease.”

Co-authors of the study are Sourav Bandyopadhyay, Katherine Licon and Janusz Dutkowski of Department of Medicine, UC San Diego; Monika Mehta and Michael-Christopher Keogh of the Department of Cell Biology, Albert Einstein College of Medicine in New York; Dwight Kuo, Ryan Chuang and Wilbert Copeland of the Department of Bioengineering, UC San Diego; Min-Kyung Sung and Won-Ki Huh of School of Biological Sciences and Research Center for Functional Cellulomics, Institute of Microbiology, Seoul National University, Republic of Korea; Eric J. Jaehnig of the Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, UC San Diego; Bernd Bodenmiller and Ruedi Aebersold of Institute of Molecular Systems Biology and University of Zurich, Switzerland; Michael Shales and Nevan J. Krogan of the Department of Cellular and Molecular Pharmacology, UC San Francisco; Dorothea Fiedler and Kevan M. Shokat of the Department of Cellular and Molecular Pharmacology, UC San Francisco and the Howard Hughes Medical Institute; and Richard D. Kolodner of the Ludwig Institute for Cancer Research and the departments of Medicine and Cellular and Molecular Medicine, and the Institute for Genomic Medicine, all at UC San Diego.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of California – San Diego. The original article was written by Scott LaFee.

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Journal Reference:

1. S. Bandyopadhyay, M. Mehta, D. Kuo, M.-K. Sung, R. Chuang, E. J. Jaehnig, B. Bodenmiller, K. Licon, W. Copeland, M. Shales, D. Fiedler, J. Dutkowski, A. Guenole, H. van Attikum, K. M. Shokat, R. D. Kolodner, W.-K. Huh, R. Aebersold, M.-C. Keogh, N. J. Krogan, T. Ideker. Rewiring of Genetic Networks in Response to DNA Damage. Science, 2010; 330 (6009): 1385 DOI: 10.1126/science.1195618

ScienceDaily (Dec. 7, 2010) — The role a key molecule plays in a plant’s ability to remember winter, and therefore bloom in the spring, has been identified by University of Texas at Austin scientists.

Many flowering plants bloom in bursts of color in spring after long periods of cold in the winter. The timing of blooming is critical to ensure pollination, and is important for crop production and for droves of people peeping at wildflowers.

One way for the plants to recognize the spring — and not just a warm spell during winter — is that they “remember” they’ve gone through a long enough period of cold.

“Plants can’t literally remember, of course, because they don’t have brains,” says Sibum Sung, assistant professor in the Section of Molecular Cell and Developmental Biology. “But they do have a cellular memory of winter, and our research provides details on how this process works.”

The process is known as vernalization, whereby a plant becomes competent to flower after a period of cold. And though it is common for many plants adapted to temperate climates, including important crops like winter wheat, it has not been until the past decade or so that scientists have begun to understand the process’s genetic and molecular underpinnings.

Sung and postdoctoral fellow Jae Bok Heo have now discovered that a long, non-coding RNA molecule, named COLDAIR, is required for plants to set up a memory of winter.

They published their work on the Arabidopsis plant in Science Express on Dec. 2.

This is how it works: In fall, a gene called FLC actively represses floral production. A random bloom in fall could be a waste of precious energy.

But after a plant has been exposed to 20 days of near-freezing temperatures, the scientists found that COLDAIR becomes active. It silences the FLC gene, a process that is completed after about 30 to 40 days of cold. With the FLC silenced as temperatures warm in the spring, other genes are activated that initiate blooming.

COLDAIR helps create a cellular memory for a plant, letting it know it has been through 30 or more days of cold.

But, how does the cold actually turn on COLDAIR?

“That is one of the next questions we have,” says Sung. “How do plants literally sense the cold?”

Answering these kinds of basic questions could lead to crop improvements and will be important to grasp as climate changes alter the length of the winter season, with possible repercussions to vernalization in plants around the world.

This research was supported with funds from the National Science Foundation and The University of Texas at Austin.

Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

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Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Texas at Austin, via EurekAlert!, a service of AAAS.

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Journal Reference:

1. J. B. Heo, S. Sung. Vernalization-Mediated Epigenetic Silencing by a Long Intronic Noncoding RNA. Science, 2010; DOI: 10.1126/science.1197349

Main Category: Genetics
Also Included In: Biology / Biochemistry
Article Date: 08 Dec 2010 – 3:00 PST

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Responding to the introduction of legislation on the patenting of human genes and biological materials to the federal parliament and its referral to a second Senate Inquiry, AusBiotech and Medicines Australia are urging those affected to contribute their views.

The legislative amendment proposed in the private member’s bill, if progressed in its current form, would exclude “biological materials which are identical or substantially identical to such materials as they exist in nature, however made” from patent protection. This would have far-reaching and possibly dire consequences for patient access, medical research and the biotechnology and medicines industry

The bill was immediately referred to the Senate Legal and Constitutional Affairs Legislation Committee for inquiry and reporting in June 2011. Those with an interest and relevant contribution to make, have until 25 February 2011 to make submissions.

AusBiotech and Medicines Australia strongly support the view that all Australians should have access to world-class medical science. However, the amendments proposed in the private members’ bill for a ban on patents for all biological materials may result in potentially life-altering products simply never being developed.

Governments are not in the business of bringing therapeutics and diagnostics to market and so we rely on a ‘social contract’ with industry and investors to provide the money and take the risks to develop novel medicines and diagnostic technologies.

The biotechnology and medicines industry does not dispute that the DNA sequences of humans exist without any intervention of man and thus are not considered inventions. The mere identification of a new gene is not sufficient to secure a patent – the threshold for patentability requires applicants to demonstrate “novelty, inventive step and usefulness”.

The inclusion of human gene sequences in a patent has never and would never give the patent owner any rights or ownership in relation to the gene(s) that exist in the human body.

The long-standing inquiry into gene patents by the Senate Community Affairs Committee released its report last week. The Committee received 78 public submissions, including submissions from AusBiotech and Medicines Australia, and conducted eight public hearings. The Report calls for a considered approach that takes into account the complexities surrounding the debate, and recommends an amendment to include a research exemption.
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With R&D programs coming at a cost of hundreds of millions of dollars, patents are an important element in the value proposition that both public and private investors consider before deciding to invest. Logically, any reduction in investment will correlate with a decrease in the number of new medicines and tests being developed. In the event that the current incentives for corporate and venture capital investment in the form of patentability disappear, the question is: Who will partner with
public research institutes and biotechnology companies to provide the money and development capability to translate Australian inventions from ‘bench to bedside’?

There is little or no significant evidence to support the contention that gene patents stifle research. A recent study concluded that of 381 scientists surveyed, none had had their work stopped by the existence of third-party patents and only about 1% had a delay or were required to modify their work, and said the fee was in the range of US$1-100. In the specific case of the Myriad gene patents, 49 Australian research organisations have published their BRCA-related results over the past 12 years.

Research activities and patents in Australia enjoy a continuing and beneficial coexistence. Nevertheless, to avoid any possibility of misinterpretation, IP Australia is currently advancing the amendment of the Patents Act to introduce a research use exemption, which was supported by the Senate inquiry’s recommendations. Both AusBiotech and Medicines Australia support the ongoing review and amendment of legislation to ensure that Australian industry and researchers have a set of clear rules to guide them as they strive to bring life-changing healthcare innovation to patients. The safeguard provisions should be reviewed to confirm they are straightforward, intelligible, not cost-prohibitive and, thereby, readily accessible to all Australians. It is important to consider the ramifications of a ban on the patenting of biological material which would extend far beyond medicine, with serious negative impacts likely on innovations to deliver benefits in the health and productivity of plants and animals, such as the development of high-yield crops.

The amendment proposed in the private members’ bill will not necessarily deliver solutions for the issues that some stakeholders are articulating. For example, as is the case with the BRCA diagnostic test, patient access to the diagnostic test will not be improved by placing a ban on gene patents. Such technologies simply may not be developed and therefore no-one will benefit.

AusBiotech is Australia’s voice on biotechnology, and represents more than 3,000 members, encompassing medicines, medical diagnostics and devices, agriculture, alternative fuels and climate change.

Source:

Medicines Australia

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Main Category: Melanoma / Skin Cancer
Also Included In: Dermatology;  Stem Cell Research;  Genetics
Article Date: 08 Dec 2010 – 2:00 PST

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In a study published in the journal Developmental Cell, Sarah Millar PhD, professor of Dermatology and Cell & Developmental Biology at the University of Pennsylvania School of Medicine, and colleagues demonstrate that a pair of enzymes called HDACs are critical to the proper formation of mammalian skin.

The findings, Millar says, not only provide information about the molecular processes underlying skin development, they also suggest a potential anticancer strategy. “Inhibition of these HDAC enzymes might be able to shut down the growth of tumors that contain cells resembling those in embryonic skin,” she says.

Acting as a barrier to infection and dehydration, the outermost layer of the skin, called the epidermis, is a stratified structure in which progenitor stem cells in the bottommost layer continuously divide to replenish the cells in the upper layers that are lost as skin cells slough off. The origin of this structure is a single cell layer called surface ectoderm that covers vertebrate embryos.

Millar’s team is interested in how surface ectoderm becomes epidermis. They decided to focus on enzymes that control gene expression by regulating the accessibility of chromatin – the DNA and protein structure in which genes reside. Within the chromatin, DNA is wound around proteins known as histones. The degree of compaction of this structure influences whether or not genes are expressed. Genes in tightly wound chromatin areas are generally inaccessible and suppressed, whereas those in “open” or loosely packed areas can be activated.

HDACs remove chemical modifications known as acetyl groups from histones, resulting in a compact and repressive chromatin environment. Previous evidence had suggested a possible role for histone acetylation in regulating epidermal development, but its exact functions were unclear.

Skin Essentials

Penn MD/PhD student Matthew LeBoeuf, the lead author of the study, deleted the genes for two HDACs in the embryonic surface ectoderm of mice, and found that in the absence of both HDAC1 and HDAC2, the epidermis fails to differentiate and the embryos die at birth. “These deacetylation enzymes, which usually act to compact the chromatin in particular regions, are absolutely essential for the skin to develop,” Millar explains.

When they examined these mutant mice, Millar’s team found that in addition to defective epidermis, the embryos also failed to develop hair follicles, tongue papillae, eyelids, and teeth – a constellation of defects that was reminiscent of deletion of another gene, called p63.

p63 is a transcription factor – a protein that activates or represses the expression of other genes. In this case, p63 is a kind of epidermal master regulator; its job is to ensure the formation of epidermis. When LeBoeuf examined the expression of known p63 targets, he found that those genes that are activated by p63 exhibit normal expression in HDAC mutant embryos, whereas those that are normally repressed by p63 do not. He also found that HDACs associate with regulatory sequences upstream of p63-suppressed genes, and are in fact active there; histone proteins from those regions are more heavily acetylated in keratinocytes treated with an HDAC inhibitor than in control-treated keratinocytes.

So, how does HDAC mutation lead to failure of epidermal development? As Millar explains, the genes that normally are repressed by p63 act to suppress cell division and induce cell aging. In HDAC mutants (as well as in p63 mutants), these cell division inhibitory proteins become active, stifling epidermal development by shutting down the division and self-renewal of the progenitor cell layer. “Normally, it’s really important that p63 shuts down these genes,” Millar says. “If it’s not doing that, then the skin can’t develop.”

Molecular Yin and Yang

Exacerbating that problem, her team determined that HDACs also normally act to inhibit the activity of a p63-related protein called p53. p53 is the yin to p63′s yang: it normally enhances the expression of proteins that suppress cell division and induce aging.

Thus, the net effect of HDAC deletion in these mice is to both prevent repression of embryonic genes that dampen stem cell proliferation, and also to actively enhance their expression.

According to Millar, these findings suggest the possibility that HDAC inhibitors – already in clinical trials for a variety of tumors – may be useful therapeutics in the fight against certain skin cancers that are characterized by the presence of undifferentiated, embryonic-like cells. She stresses, however, that experiments on tumors were not performed in the current study. “This is more of a future direction,” she says, “something our results imply.”

Notes:

Other authors include Anne Terrell, Sohum Trivedi, Jonathan Epstein, and Edward Morrisey at Penn; Satrajit Sinha of the State University of New York, Buffalo; and Eric Olson of the University of Texas Southwestern Medical Center, Dallas.

Dr. Millar’s research is funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Institute of Dental and Craniofacial Research, and the National Institute of Child Health and Human Development.

Source:
Karen Kreeger

University of Pennsylvania School of Medicine

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Main Category: Cardiovascular / Cardiology
Also Included In: Genetics;  Biology / Biochemistry
Article Date: 08 Dec 2010 – 2:00 PST

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A gene that can cause congenital heart defects has been identified by a team of scientists, including a group from Princeton University. The discovery could lead to new treatments for those affected by the conditions brought on by the birth defect.

Princeton researchers focused on identifying and studying the gene in zebrafish embryos, and the team’s work expanded to include collaborations with other groups studying the genetics of mice and people.

“This work really showcases the use of collaborative science and multiple model systems to better understand human disease,” said Rebecca Burdine, an assistant professor of molecular biology at Princeton who led her team.

The newly discovered gene, called CCDC40 (for “coiled coil domain containing protein 40″), controls right-to-left patterning as tissues develop, a critical factor in the configuration and effectiveness of organs. Scientists found the gene by zeroing in on zebrafish and mice in which the placement, and sometimes the internal structure, of organs is disrupted or reversed. While these so-called “left-right patterning” defects occur very rarely in zebrafish and mice, they occur at high frequency in the animals with mutated CCDC40 genes. Their study was published online in Nature Genetics. A separate paper by another group identifying a sister gene, CCDC39, based on studies of genes in sheepdogs, appears in the same edition of the science journal.

“We used the strengths of different model organisms to gain an understanding of how a novel protein, produced by this new gene, functions,” said Irene Zohn, who led a research group studying mice genetics at the Children’s National Medical Center in Washington, D.C., and is one of the first authors on the CCDC40 study with Burdine’s group. A third group, led by physician Heymut Omran and based at University Hospital in Freiburg, Germany, rounded out the team, with other individual participants located elsewhere. “These findings would not have been possible without the collaborations between the three groups,” Zohn added.

The collaboration started several years ago when Zohn contacted Burdine, a renowned expert in the study of left-right patterning in animals. Developmental biologists such as Burdine investigate what factors contribute to patterns in vertebrates relating to symmetry and leading to where organs are placed in the spatial configuration of the body. In humans and many animals, for example, the heart is usually situated on the left side with the liver at its lower right. Flaws in left-right patterning can lead to congenital heart defects in humans.

It is estimated that one in 10,000 people have a condition known as situs inversus, when the left-to-right patterning in the body is switched. In most cases, there are no adverse consequences of this condition, but problems arise when perturbations in the patterning signals produce reversals within organs, including heart structures such as the aorta and pulmonary artery. In rare circumstances, the heart can be located on one side without any supporting structures around it such as arteries and veins. That condition can be fatal.

Zohn and her research team had found a gene in mice that, when mutated, appeared to lead to disruptions in left-right patterning causing heart defects. She asked Burdine if she could locate a similar gene in zebrafish. When Burdine studied the mouse gene found by Zohn’s team and its location in the spool of genetic matter known as the genome, Burdine realized that her team knew of a gene mutation in zebrafish that was in the same general area of the zebrafish genome. Upon further study, however, Burdine and her team found that the mouse and zebrafish genes were not only in the same general area of their relative genomes — they were the same gene.

At that point, the teams tracked where the genes were expressed in mice and fish to better understand their function. The groups found that the genes were specifically turned on in cells that produce motile cilia, important hair-like fibers that project from the surface of cells.

Burdine reasoned that zebrafish embryos with the mutated version of the gene also should possess some sort of defect in the cilia themselves. However, views of the cilia in zebrafish embryos through normal lab microscopes showed nothing beyond the ordinary.

For a closer look, Burdine employed a special transmission electron microscope. She examined the microscopic cilia in the zebrafish with the mutation in CCDC40 and compared those images with zebrafish with the normal gene. The cilia in the zebrafish with the mutations “were disrupted in their structure in a way I had never seen before,” Burdine said.

She sent the images to Omran, who was treating people with a disorder known as primary ciliary dyskinesia or PCD. These patients suffer from a defect in the action of the cilia lining the respiratory tract. Normally, cilia beat rhythmically, moving mucus toward the throat. If cilia are impaired, however, they cannot reduce or remove mucus from the lungs, leaving people with the disorder susceptible to chronic recurrent respiratory infections, including bronchitis and pneumonia. Since motile cilia also are required for proper left-right patterning, these patients also often have defects in organ positioning.

Of the 26 patients with similar cilia structural defects tested by Omran, some 17 were found to have mutated versions of the gene CCDC40. In addition to the respiratory ciliary disorder, the patients also suffered from congenital heart defects. This finding provided evidence of a link between the cilia-induced respiratory disorder and the heart problems.

By knowing the gene and the properties conferred by its mutated version, scientists may be able to better treat those with the mutant gene and its accompanying respiratory disorders. Researchers eventually may be able to devise genetic repairs to impaired cilia, Burdine said. Because some congenital heart defects can be surgically repaired, it will be important for those individuals to understand whether or not they may be at risk for passing their defect on to their own children. In the future, it may be possible to screen for mutations in CCDC40 to help determine the risk of congenital heart defects.

Notes:

In addition to Burdine, Princeton scientists on the paper included: Noriko Okabe, a former postdoctoral fellow; Kari Baker Lenhart and Jason McSheene, graduate students; and Jessica Sullivan-Brown, a former graduate student, all in the Department of Molecular Biology.

In the United States, teams included those at: the Children’s National Medical Center in Washington, D.C.; the Howard Hughes Medical Institute at the University of Colorado in Denver; and the Sloan-Kettering Institute in New York. In Germany, teams included those at: the University Hospital Freiburg; the Klinik und Poliklinik für Kinder- und Jugendmedizin-Allgemeine Pädiatrie-Universitätsklinikum in Münster; Albert-Ludwigs-University in Freiburg; the Max Planck Institute for Plant Breeding Research in Köln; and the Max Planck Institute for Developmental Biology in Tübingen. Other groups were based at: the National Medical Center and the Pediatric Institute Svabhegy, both in Budapest, Hungary; and Copenhagen University Hospital in Denmark.

Support for the research included funding from the American Recovery and Reinvestment Act, the federal economic stimulus bill enacted last year, and also from the National Institute of Child Health and Human Development of the National Institutes of Health, the March of Dimes Foundation, the Spina Bifida Association, the German Human Genome Project and the Howard Hughes Medical Institute.

Source:
Kitta MacPherson
Princeton University

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Main Category: Immune System / Vaccines
Also Included In: Genetics
Article Date: 08 Dec 2010 – 1:00 PST

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If a strand of your DNA was stretched out completely, it would be more than six feet long. It’s hard to imagine that it can fit inside the nucleus of one of your cells, but that’s exactly how it works.

For much of the last century, scientists have been busy figuring out how DNA is packaged in cells, and have found strong indications that the packaging is integral to how DNA works. The packaging – comprised mostly of an amino acid molecule called a histone – influences the on and off switches of different genes that regulate cellular function and play a role in human diseases ranging from cancer to genetic disorders. Scientists study histones by using antibodies to specific “flavors” of histones that are only very slightly different from one another. The antibodies help to pinpoint what DNA is being packaged by a certain kind of “flavor” of histone, and how that affects gene regulation. Different flavors affect genes differently.

“And this is where it gets complicated,” says Jason Lieb, PhD, who led the project. “Many companies make these antibodies that we scientists use in our labs – but there are so many different kinds of histones and types of tests we do that it’s just not feasible for the companies to anticipate every single way that a given antibody can be used.”

This is a problem, explains Lieb, who is a professor of biology at UNC-Chapel Hill and member of UNC Lineberger Comprehensive Cancer Center, since scientists can’t be absolutely certain that the antibody is recognizing a specific “flavor” of histone, or one that is very closely related.

“Histones are essentially the key to the DNA library. They tell you which ‘shelves’ of that library – or areas of the genome – are open or closed to information moving in and out. But since the differences between the different ‘flavors’ of histones are often extremely small, and it’s likely that an antibody may react with more than one histone or in different ways depending on the type of test being used in the lab. It makes scientific precision very difficult,” Lieb notes.

In a paper published in the journal Nature Structural and Molecular Biology, Lieb and his colleagues from across the country describe how they tested more than 200 antibodies against 57 histone modifications (or flavors) in three different organisms, using three different tests commonly used in this kind of genetic analysis. They found that about 25 percent of antibodies currently sold have a problem with specificity – targeting the anticipated histone – in a given test. They believe that this proportion is likely to remain steady over time.

“So we thought, ok, we need to help ourselves as scientists. We set up a web-based searchable database. Our results are there and other scientists can also post their results so that we have a self-sustaining, up-to-date source of information that is really important to scientists working to understand a broad range of genetic phenomena,” he said.

The research was funded by the National Human Genome Research Institute (part of the United States National Institutes of Health) and included researchers from the Universities of California at Santa Cruz, Berkeley, and San Diego, the Lawrence Berkeley National Laboratory, the Ludwig Institute for Cancer Research, Harvard Medical School, the University of Cambridge (UK), Washington University in St. Louis, Ontario Institute for Cancer Research (Canada) and Rutgers University.

Source:
Ellen de Graffenreid
University of North Carolina School of Medicine

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Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Stem Cell Research;  Transplants / Organ Donations;  Genetics
Article Date: 08 Dec 2010 – 0:00 PST

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Over the past decade, significant advances have been made in the treatment of leukemia through the ongoing development of gene-based targeted therapies. Research presented at the 52nd Annual Meeting of the American Society of Hematology provides greater understanding of the optimal use of several BCR-ABL inhibitors for the treatment of acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML), and how a new gene target functions for several myeloid malignancies.

“Each year, we continue to make significant strides in better understanding the underlying role certain genes play in the development of various forms of leukemia,” said moderator of the press conference Peter Emanuel, MD, Director of the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock. “These studies underscore the advances we are making to develop a new generation of treatment options that will improve overall outcomes for our patients.”

Imatinib Significantly Enhances Long-Term Outcomes in Philadelphia Positive Acute Lymphoblastic Leukemia; Final Results of the UKALLXII/ECOG2993 Trial [Abstract 169]

Acute lymphoblastic leukemia (ALL), a cancer of the white blood cells, is the most common type of leukemia, with about 3,930 new cases diagnosed each year in the United States.1 According to researchers, approximately 20 to 25 percent of all adults with ALL have a genetic abnormality in which some genetic material from chromosome 9 switches position with some genetic material from chromosome 22. This condition is known as Philadelphia chromosome-positive (Ph+) ALL, which is a rapidly progressive form of leukemia. It is associated with a poor prognosis since induction chemotherapy alone does not produce prolonged remissions. Therefore, an allogeneic stem cell transplant, in which a patient receives stem cells from a sibling or unrelated matched donor, is often recommended after the first complete remission.

In 1993 researchers from the National Cancer Research Institute in the United Kingdom and the Eastern Cooperative Oncology Group in the United States initiated a study to evaluate whether allogeneic stem cell transplant is an effective treatment option for adult patients with Ph+ ALL. In this study, 266 patients received two phases of induction chemotherapy followed by an allogeneic stem cell transplant (“pre-imatinib” arm). Following the availability of imatinib, a targeted BCR-ABL inhibitor, the purpose of the study was modified in 2003 to include and evaluate the use of imatinib as part of consolidation therapy prior to an allogeneic stem cell transplant (“late-imatinib” arm) or as part of standard induction therapy prior to the transplant (“early-imatinib” arm). Results from the pre-imatinib cohort (Fielding, Blood 2009) were then used as a benchmark for use of imatinib in patients with Ph+ ALL.

In the late-imatinib arm of the study, 86 patients received imatinib 600 mg a day as part of consolidation therapy prior to undergoing an allogeneic stem cell transplant following two induction chemotherapy regimens. Those in the early-imatinib arm (89 patients) were given imatinib 600 mg earlier as part of the second chemotherapy induction phase prior to the allogeneic stem cell transplant. All patients who received an allogeneic stem cell transplant in the study were given imatinib for two years post-transplant. If a transplant was not feasible for any reason, imatinib could be given as a maintenance therapy for two years.

Results from this study, the largest international study of patients with Ph+ ALL evaluating allogeneic stem cell transplantation (control group) and the use of imatinib, show significant differences in outcomes between the three different groups after three years of follow-up. The researchers found that overall survival reached 25 percent in the pre-imatinib arm, 34 percent in the late-imatinib arm, and 48 percent in the early-imatinib arm. Event-free survival was 19 percent in the pre-imatinib arm, 29 percent in the late-imatinib arm, and 35 percent in the early-imatinib arm. Additionally, relapse-free survival reached 36 percent, 45 percent, and 62 percent respectively.

Prior to the introduction and availability of imatinib, only 28 percent of patients went on to receive an allogeneic stem cell transplant per the study protocol. In these pre-imatinib patients, five-year overall survival was 40 percent for those patients who received an allogeneic stem cell transplant compared with 19 percent for non-transplanted patients. Of patients in the “late” and “early” arms who received imatinib, 44 percent were able to undergo the allogeneic stem cell transplant. Three-year overall survival was 59 percent for these transplant patients compared with 28 percent for those who did not receive a transplant.

“The Philadelphia chromosome is the single most common chromosome abnormality for adults with ALL, and therefore it is important to know that a targeted therapy like imatinib can help improve outcomes in these patients,” said lead study author Adele K. Fielding, MBBS, PhD, FRCPath, FRCP, Senior Lecturer, University College London. “These study results demonstrate for the first time that there is a long-term survival advantage of being treated with imatinib earlier in the treatment protocol.”

Excellent Outcomes at 3 Years With Nilotinib 800 mg Daily in Early Chronic Phase, Ph+ Chronic Myeloid Leukemia (CML): Results of a Phase 2 GIMEMA CML WP Clinical Trial [Abstract 359]

It is estimated that the incidence rate of chronic myeloid leukemia (CML), a type of blood and bone marrow malignancy in which too many white blood cells are produced, varies from 0.6 to 2 cases per 100,000 persons each year.2 More than 95 percent of people with CML are affected with the Philadelphia chromosome (Ph+), a unique chromosomal abnormality that harbors a leukemic gene called BCR-ABL. This gene promotes the disease and allows the disease to progress to terminal acute leukemia – defined as “accelerated” and “blast” phase – if the disease is not properly treated. The current standard first-line treatment for Ph+ CML is the targeted BCR-ABL inhibitor, imatinib.

Nilotinib, a second-generation BCR-ABL inhibitor, recently received FDA approval (June 2010) as a first-line therapy for this patient population based on the results from an 18-month study that found that nilotinib demonstrated superior efficacy as compared with standard therapy imatinib, with higher and faster molecular responses. This study also showed that rates of progression to accelerated or blast phase were also significantly lower for nilotinib than for imatinib.

In order to confirm that the efficacy of nilotinib is durable over a three-year time frame, the period of time when most of the failures to imatinib are described, researchers from the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Chronic Myeloid Leukemia (CML) Working Party (WP) in Italy enrolled 73 patients with newly diagnosed Ph+ CML into a phase II clinical trial in which patients received nilotinib 400 mg twice daily. Currently, the median follow-up is longer than three years. The primary endpoint of the study was the complete cytogenetic response (CCgR) rate at 12 months – meaning that no cells containing the Philadelphia chromosome were detected in the bone marrow. Other outcomes evaluated in the study included overall survival, progression-free survival, failure-free survival, and event-free survival.

At different key milestones throughout the study, the CCgR rate was high (78 percent at three months, 96 percent at six, 12, and 18 months). Within 12 months, the cumulative CCgR rate for study participants was 100 percent, which means that all patients achieved CCgR at least once. Additionally, after a median follow-up of 36 months, overall survival, progression-free survival, and failure-free survival reached 99 percent for each, and event-free survival was 92 percent. The cumulative major molecular response (MMR) rate, a more sensitive measurement of response, was 96 percent at 12 months. The MMR rate was 52 percent at three months, 66 percent at six months, 85 percent at one year, 81 percent at 18 months, and 82 percent at two years. In patients who achieved an MMR, none progressed to accelerated or blast phase CML. Furthermore, only one patient in the entire study progressed to accelerated or blast phase due to the development of another BCR-ABL mutation called a T315I mutation.

“While it is important to rapidly induce responses in these patients, it is also important that these responses last as long as possible,” said lead study author Gianantonio Rosti, MD, Scientific Secretary of the GIMEMA CML WP, Department of Hematology and Oncology, University of Bologna, Bologna, Italy. “Results from this study not only show that nilotinib quickly induces high rates of response, but responses also are durable and stable beyond three years, translating into optimal outcomes for newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia.”

A Phase I Trial of Oral Ponatinib (AP24534) in Patients With Refractory Chronic Myelogenous Leukemia (CML) and Other Hematological Malignancies: Emerging Safety and Clinical Response Findings [Abstract 210]

Despite the recent advances in the treatment of chronic myeloid leukemia (CML) over the past decade with both first- and second-generation BCR-ABL inhibitors, there are patients who continue to fail two or more of these therapies and/or develop a mutation called T315I, which alters the shape of the ABL enzyme, making these patients unresponsive to current therapies. Currently, there are no effective treatment options for patients who develop a T315I mutation. Pre-clinical research has demonstrated that ponatinib, an investigational pan-BCR-ABL inhibitor, may inhibit the entire spectrum of mutations that cause resistance to other BCR-ABL inhibitors.

Researchers at The University of Texas MD Anderson Cancer Center in Houston, in collaboration with colleagues from other institutions in the United States, initiated an open-label, dose escalation phase I study to assess the safety and investigate the anti-leukemic activity of ponatinib. A total of 67 patients with various refractory hematologic malignancies including CML, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML), were enrolled in the study to receive a daily oral dose of ponatinib. A large majority of patients with Ph+ CML had previously failed treatment with other BCR-ABL inhibitors (imatinib: 96 percent, dasatinib: 89 percent, nilotinib: 55 percent, more than two previous therapies: 95 percent, and more than three previous therapies: 64 percent). Additionally, 72 percent of all patients enrolled in the study had BCR-ABL mutations, with 38 percent (23 patients) having a T315I mutation and 12 percent (7 patients) having an F317L mutation.

To date, patients enrolled in the study have received up to 60 mg doses of ponatinib with 64 percent (43 patients) remaining on therapy and 36 percent (24 patients) discontinuing therapy. Of 32 evaluable patients with CML in chronic phase, 30 patients (94 percent) had a complete hematologic response (meaning blood cell counts are in the normal range), and 20 patients (63 percent) had a major cytogenetic response (meaning that no cells containing the Philadelphia chromosome were detected in the bone marrow). Of those achieving a major cytogenetic response, 12 patients had a complete cytogenetic response and eight patients had a partial cytogenetic response. Eighteen of these patients remained on ponatinib for a mean duration of 326 days without progression (range 142 to 599 days) with 13 of these patients having a confirmed response at a second assessment.

Of 11 evaluable patients with CML in chronic phase with a T315I mutation, 11 patients (100 percent) achieved a complete hematologic response and nine patients (82 percent) had a major cytogenetic response (eight of these patients had a complete cytogenetic response). Of 16 evaluable patients with either CML in accelerated or blast phase or with Ph+ ALL, five patients (31 percent) had a major hematologic response, three patients (19 percent) had a major cytogenetic response, and one patient (6 percent) had a minor cytogenetic response. Of nine evaluable patients with CML in accelerated or blast phase or patients with Ph+ ALL with a T315I mutation, three patients (33 percent) had a major hematologic response, and two patients (20 percent) had a major cytogenetic response.

Responses also were seen in heavily refractory patients with no mutations as well as in patients with other mutations who were resistant to currently approved tyrosine kinase inhibitors. For example, there was one complete cytogenetic response and one partial cytogenetic response in two patients with an F317L mutation who had previously failed therapy with imatinib, dasatinib, and nilotinib. Another patient with an F359C mutation who failed both imatinib and nilotinib therapy achieved a complete hematologic response and a complete cytogenetic response with ponatinib. Overall, 13 out of 60 patients (22 percent) with Ph+ disease achieved a major molecular response, including 12 out of 42 patients (28 percent) with CML in chronic phase and six out of 15 patients (40 percent) with T315I mutation confirmed at the start of the study. Twelve major molecular responses occurred in patients who received ponatinib for four months or less. There were four major molecular responses in patients who received ponatinib for only two months or less. Major molecular responses also were seen in patients with the following mutations: M351T, F359C, F317L, M244V, and G250E.

“These results are exciting because it is very difficult to induce responses, particularly at the high rates seen with ponatinib, in heavily refractory patients,” said lead study author Jorge Cortes, MD, Deputy Chair and Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center in Houston. “While these results need to be confirmed in a larger study, ponatinib may be the next step in coming closer to overcoming, and possibly preventing, the most difficult mechanisms of resistance in CML, and ultimately finding a cure for Philadelphia chromosome-positive leukemias.”

Impaired Hydroxylation of 5-Methylcytosine in TET2 Mutated Patients With Myeloid Malignancies [Abstract 1]

In previous research, mutations in the TET2 (Ten-Eleven Translocation-2) gene were found across a broad range of myeloid malignancies, but little is known about the pathologic consequences of this mutation or the role it plays in the development of diseases such as myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia.

A team of scientists at the Taussig Cancer Institute at the Cleveland Clinic in Ohio and Dana-Farber Cancer Institute at Harvard University initiated several specialized experiments on leukemic cancer cells carrying TET2 gene mutations. TET2 mutations occurred throughout the entire TET2 gene and led to its inactivation. Functional studies showed that the TET2 mutations likely alter epigenetic regulation.

Epigenetic alterations are a form of chemical modification of the DNA strand that naturally occurs during normal tissue maturation, but is disturbed in cancer. One key epigenetic mechanism is the methylation of cytosines (one of the four building blocks of DNA), which effectively blocks or “silences” particular genes.

Experimental results demonstrate that the TET2 gene alters the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, which likely in turn affects the silencing function of 5- methylcytosine. TET2 mutations, or experimentally decreased TET2 levels, resulted in lower hydroxymethylcytosine levels and perturbed maturation of bone marrow stem cells.

“The process of methylation or ‘silencing’ of genes can be altered in disease or through application of epigenetic drugs. Identification of the variant of cytosine, 5-hydroxymethylcytosine, introduces a new mechanism of epigenetic regulation that has never been explored,” said senior study author Jaroslaw P. Maciejewski, MD, PhD, FACP, Chairman, Department of Translational Hematology and Oncology Research, Taussig Cancer Institute at the Cleveland Clinic in Ohio. “The mutation in TET2 is an important, common mutation associated with leukemia that affects epigenetics, and now we are closer to deciphering the functional consequences of this mutation. It is likely that 5-hydroxymethylcytosine levels may become a disease biomarker and possibly molecular target for the development of new therapies.”

References

1.
The Leukemia & Lymphoma Society. Acute Lymphocytic Leukemia. Accessed November 10, 2010.
2.
Rohrbacher M, Hasford J, Epidemiology of chronic myeloid leukaemia (CML). Best Practice & Research Clinical Haematology 2009; 22: 295-302.

Source:
Lindsey Love
American Society of Hematology

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ScienceDaily (Dec. 7, 2010) — Quantitative trait loci affecting egg quality — albumen thickness, blood and meat spots, fishy taint and shell durability — were identified through the mapping of the chicken genome. The results of a recent doctoral study enhance the efficiency of chicken breeding.

In her doctoral study, MTT Research Scientist Mervi Honkatukia charted chromosomal areas of the genotype that affect egg albumen quality. One of the areas was divided into two distinct parts, both of which had an impact on albumen quality.

“Thick albumen is considered to be a sign of freshness. Biochemical reactions cause albumen thinning as the egg ages, but sometimes even the albumen of fresh eggs is thin. This is a hereditary trait,” Honkatukia says.

Pores or fractures in the egg shell may allow microbes to enter the egg. The yolk is susceptible to contamination; the albumen ‘anchors’ the yolk in place at the centre of the egg to prevent contact with the shell.

Spots eliminated through breeding

Blood and meat spots are internal quality defects sometimes found in eggs. Although they do not involve a risk to human health, they may slightly raise the egg infection risk and lower the reproductive performance of eggs for hatching. Spots are primarily an aesthetic problem.

The study was the first reported study to employ gene mapping tools to blood and meat spots. It was discovered that there is a link between susceptibility to blood and meat spots and a specific region of chromosome Z; the candidate gene ZO-2 located in the region and the gene’s internal regulation factors appeared to have an impact on the prevalence of blood and meat spots in different populations.

“Although the quantitative trait loci only explain around two per cent of phenotypic variance, any genetic progress achieved through breeding is permanent and cumulative, in other words, produces a compound impact from generation to generation. The results can be used in breeding selection to root out undesirable traits,” the research scientist summarises.

In addition to genotype, the living conditions of chickens also affect the frequency of blood and meat spots: an incorrect diet, temperature fluctuations and sudden noises increase the occurrence of spots.

Fishy taint is a gene defect

Honkatukia’s third research area was the fishy-taint problem, which a quality issue triggered by feed made from rapeseed, for example. A 2005 study by MTT used gene mapping tools to identify the gene defect causing the quality-reducing odour defect. Honkatukia’s dissertation expands on that study.

“The simple feather test we developed can be used to determine whether a specimen has a gene defect and whether an unaffected specimen is carrying a gene defect. The results have been patented; the breeding company owning the patent, Lohmann Tierzucht GmbH, has also applied the results to practice.”

Information on genotype and DNA markers enable the identification of hereditary traits at an early stage, long before their manifestation. This enables increased breeding efficiency. Gene markers are also helpful when a specific trait is gender-confined or can only be assessed for one gender. This makes it easier to root out quality defects.

“The reduction in the number of discarded eggs achieved through gene testing improves the profitability of egg producers. Those who stand to gain the most out of all this are quality-conscious consumers,” Honkatukia concludes.

Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

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Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by MTT Agrifood Research Finland, via AlphaGalileo.

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