Mutations in leukemia gene linked to new childhood growth disorder

Mutations in a gene associated with leukemia cause a newly described condition that affects growth and intellectual development in children, new research reports.A study led by scientists at The Institute of Cancer Research, London, identified mutations in the DNA methyltransferase gene, DNMT3A, in 13 children.All the children were taller than usual for their age, shared similar facial features and had intellectual disabilities. The mutations were not present in their parents, nor in 1,000 controls from the UK population.The new condition has been called ‘DNMT3A overgrowth syndrome’.The research is published today in the journal Nature Genetics and is a part of the Childhood Overgrowth Study, which is funded by the Wellcome Trust, and aims to identify causes of developmental disorders that include increased growth in childhood. The DNMT3A gene is crucial for development because it adds the ‘methylation’ marks to DNA that determine where and when genes are active.Intriguingly, DNMT3A mutations are already known to occur in certain types of leukemia. The mutations that occur in leukemia are different from those in DNMT3A overgrowth syndrome and there is no evidence that children with DNMT3A mutations are at increased risk of cancer.Researchers at The Institute of Cancer Research (ICR), with colleagues at St George’s, University of London, The Royal Marsden NHS Foundation Trust, and genetics centres across Europe and the US, identified the mutations after analysing the genomes of 152 children with overgrowth disorders and their parents.Study leader Professor Nazneen Rahman, Head of Genetics and Epidemiology at The Institute of Cancer Research, London, and Head of Cancer Genetics at The Royal Marsden NHS Foundation Trust, said: “Our findings establish DNMT3A mutations as the cause of a novel human developmental disorder and add to the growing list of genes that appear to have dual, but distinct, roles in human growth disorders and leukemias.”The new discovery is of immediate value to the families in providing a reason for why their child has had problems. Moreover, because the mutations have arisen in the child and have not been inherited from either parent, the risk of another child in the family being similarly affected is very low. This is very welcome news for families.Study co-leader Dr Katrina Tatton-Brown, Clinical Researcher at The Institute of Cancer Research, London, and Consultant Geneticist at St George’s, University of London, said: “Having a diagnosis can make a real difference to families — I recently gave the result back to one of the families in which we identified a DNMT3A mutation and they greatly appreciated having a reason for their daughter’s condition after many years of uncertainty.”Story Source:The above story is based on materials provided by Institute of Cancer Research. Note: Materials may be edited for content and length.

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Collagen clue reveals new drug target for untreatable form of lung cancer

Aug. 29, 2013 — Collagen, the stuff of ligaments and skin, and the most abundant protein in the human body, has an extraordinary role in triggering chemical signals that help protect the body from cancer, a new study reveals.Scientists at The Institute of Cancer Research, London, have uncovered a series of chemical signals sent out by collagen that appear to protect against cancer’s growth.Boosting those signals could act as an effective treatment for cancers that grow in the presence of collagen, including squamous cell lung cancer, for which no targeted treatments currently exist.And the findings suggest that switching off these chemical signals, as some treatments for leukemia do, is likely to be counter-productive in cancers where interaction with collagen plays an important role.The study was funded by The Institute of Cancer Research (ICR), the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC).The ICR team explored the role of signals triggered by collagen in human embryonic kidney cells, a type of cell often used in studies of this type. They analysed the role of a molecule called DDR2, which relays signals from collagen as a means of maintaining tissue structure and function, and is mutated in some forms of squamous cell lung cancer.They treated cells with collagen, and found that DDR2 responded by activating a second protein called SHP-2, in a process that appears to be important in protecting against the growth of some cancers. But a specific mutant form of DDR2 present in some squamous cell lung cancers seemed unable to signal through SHP-2, suggesting the loss of function had left the tissue vulnerable to cancer growth.That finding offers an exciting opportunity to design the first targeted treatments for squamous cell lung cancer, perhaps by mimicking the action of SHP-2 to re-erect the normal controls against cancer’s growth in the presence of collagen.Dr Paul Huang, Team Leader in Protein Networks at The Institute of Cancer Research, said: “We knew collagen was capable of slowing the growth of some cancer types, presumably by maintaining the structure of tissues, but our new study for the first time identifies how this effect occurs in lung cancer.”We sifted through data on 428 different proteins stimulated by collagen, and isolated just one we think can play a key role in protecting tissues from cancer. Identifying this molecular trigger opens up the prospect of targeted treatments for squamous cell lung cancer.”Importantly, we also highlighted the duplicitous nature of this important signalling network. Although we know it directs a lot of cellular processes that can contribute to cancer — such as differentiation, proliferation and motility — in the presence of collagen, it actually seems to protect against cancer. That means we will need to treat cancers that develop in collagen-rich environments differently to blood cancers such as leukemia.”Professor Alan Ashworth, Chief Executive of The Institute of Cancer Research, said: “Survival rates for lung cancer remain extremely poor, and one of the ways to improve this is to discover new ways of targeting the disease with drugs. This new study is valuable for two reasons — it identifies an exciting new potential route for treating lung cancers, and it also shows us why some other approaches are unlikely to work.”Scientifically, these results are very interesting as they demonstrate how one of the most common proteins in the human body plays a role not only in building the structure of tissues but also in cancer.”

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Scientists detail critical role of gene in many lung cancer cases

Aug. 29, 2013 — Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that a well-known cancer-causing gene implicated in a number of malignancies plays a far more critical role in non-small cell lung cancer, the most common form of the disease, than previously thought.These findings establish the gene as a critical regulator of lung cancer tumor growth. This new information could turn out to be vital for the design of potentially new therapeutic strategies for a group of patients who represent almost half of non-small cell lung cancer cases.In the study, published online ahead of print by the journal Cancer Research, the scientists found that presence of known oncogene Notch 1 is required for survival of cancer cells. In both cell and animal model studies, disabling Notch 1 leads to a rise in cancer cell death.”While Notch signaling has emerged as an important target in many types of cancer, current methodologies that target that pathway affect all members of the Notch family, and this has been associated with toxicity,” said Joseph Kissil, a TSRI associate professor who led the study. “We were able to identify Notch 1 as the critical oncogene to target, at least in a common form of lung cancer.”The new findings show that Notch1 is required for initial tumor growth, as it represses p53, a well-known tumor suppressor protein that has been called the genome’s guardian because of its role in preventing mutations. The p53 protein can repair damaged cells or force them to die through apoptosis — programmed cell death.Using animal models, the study shows that inhibition of Notch1 signaling results in a dramatic decrease in initial tumor growth. Moreover, disruption of Notch 1 induces apoptosis by increasing p53 stability — substantially increasing its biological half-life, for example.These findings provide important clinical insights into the correlation between Notch1 activity and the poor prognosis of non-small cell lung cancer patients who carry the non-mutated form of the p53 gene. “If you look at lung cancer patient populations, Notch signaling alone isn’t a prognostic indicator, but if you look at p53-positive patients it is,” Kissil said.

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Could sleeping stem cells hold key to treatment of aggressive blood cancer?

July 29, 2013 — Scientists studying an aggressive form of leukemia have discovered that rather than displacing healthy stem cells in the bone marrow as previously believed, the cancer is putting them to sleep to prevent them forming new blood cells.The finding offers the potential that these stem cells could somehow be turned back on, offering a new form of treatment for the condition, called Acute Myeloid Leukemia (AML). The work was led by scientists at Queen Mary, University of London with the support of Cancer Research UK’s London Research Institute.Around 2,500 people are diagnosed with AML in the UK each year, both young and old. Although AML is curable in some the majority die from this disease.Normally, the bone marrow produces haematopoietic stem cells which mature into “adult” blood cells. In people with AML the bone marrow is invaded by leukaemic myeloid cells which aren’t able to develop into normal functioning blood cells.The result is that the body does not have enough red blood cells or platelet cells, which can cause symptoms of anemia, such as tiredness, and increase the risk of excessive bleeding. Patients are also more vulnerable to infection as the white blood cells, which fight bacteria and viruses, are not properly formed.Dr David Taussig, from the Barts Cancer Institute at Queen Mary, University of London, who led the research, said: “The widely accepted explanation has held that AML causes bone marrow failure by depleting the bone marrow of normal haematopoietic stem cells by killing or displacing them.”However, we have found that samples of bone marrow in both mice models and patients with AML contain the same, or more, of these normal stem cells than usual. So the cancer isn’t getting rid of them, instead it appears to be turning them off so they aren’t going on to form healthy blood cells.”If we can find out how the cancer cells are doing this, we can look at exploiting it to find ways to wake these stem cells up. This is very important as, while the cure rate for younger patients can be around 40 per cent, in older patients it is much lower. The treatments we have, such as chemotherapy and bone marrow transplants, just aren’t very successful in this older patient group.”The scientists studied the levels of haematopoietic stem cells (HSC) in the bone marrow of mice transplanted with human AML. They found the numbers of normal mouse HSCs stayed the same, however what did change was that the HSCs were no longer going through the stages of development which finally results in the formation of new blood cells.The findings were confirmed by the analysis of bone marrow from 16 patients with AML.Professor Peter Johnson, Cancer Research UK’s chief clinician, said: “Although major progress has been made in treating AML over the years, there’s still an urgent need for more effective treatments to improve long-term survival. This study takes us an important step forwards in our understanding of what’s going on in the bone marrow of people with AML, an area that we have not known enough about previously, and the challenge now is to turn this understanding into new treatments for patients.”Dr Taussig added: “Usually when the body is stressed, the stem cells become very active. …

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New gene involved in obesity: Link between telomeres and obesity discovered

June 20, 2013 — The discovery of an unexpected function for a gene that was associated to another process in the organism might be a solution in search of a problem, a clue to unsuspected connections. That is what has happened with RAP1, a gene that protects telomeres — the ends of chromosomes — after researchers from the Spanish National Cancer Research Centre (CNIO) surprisingly discovered its key role in obesity.”We still don’t know what evolutionary significance to attach to it, but it is at the very least interesting that a telomere gene is related to obesity,” says Maria Blasco, CNIO director and co-author of the study published today in the journal Cell Reports.RAP1 forms part of the shelterin complex, a group of proteins that make up the protective hood of telomeres — the DNA sequence at the ends of chromosomes that shortens with each cellular division and thus measures the ageing of the organism. There are six shelterins, and CNIO’s Telomeres & Telomerase Group, which studies them in-depth, has discovered that RAP1, contrary to the rest, is not essential for the survival of the organism; but that does not mean RAP1 is not important. The reverse is rather the case: when comparing the genomes of different species, it can be observed that RAP1 is the most conserved shelterin of all. Despite the long history of evolutionary changes, RAP1 has not changed; it is present even in yeast. This normally implies an important role in the organism, but which one?CNIO researchers had discovered that RAP1, in addition to being located in telomeres, is also present in the rest of the chromosome; they supposed it acts regulating the action of other genes. In order to analyse this other potential function, and its importance in the organism, CNIO researchers created a lineage of mice without RAP1 and, to their surprise, discovered a model for obesity.MICE LACKING RAP1 GAIN MORE WEIGHT”Mice — especially female mice — without RAP1 do not eat more, but do gain weight. They suffer from metabolic syndrome, accumulate abdominal fat and present high glucose and cholesterol levels, amongst other symptoms,” says Paula Martínez, first-author of the study.The reason is that RAP1 plays an important role in the regulation of genes involved in metabolism. In particular, researchers have discovered that it acts on the same signalling pathway mediated by another protein: PPAR- gamma (PPAR-γ). In fact, PPAR-γ deficient mice suffer from a type of obesity “surprisingly similar” to that seen in mice without RAP1.The next step in the research will be to study if RAP1 also plays a role in human obesity. …

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Changes in cell shape may lead to metastasis, not the other way around

June 21, 2013 — A crucial step toward skin cancer may be changes in the genes that control cell shape, report a team of scientists from The Methodist Hospital Research Institute, the Institute of Cancer Research, London, and Harvard Medical School in an upcoming issue of Nature Cell Biology (now online).Using automated high content screening and sophisticated computational modeling, the researchers’ screening and analysis of tens of millions of genetically manipulated cells helped them identify more than a dozen genes that influence cell shape. Their work could lead to a better understanding of how cells become metastatic and, eventually, pinpoint new gene therapy targets for cancer treatment.”We found that by altering the way the cells are grown to better mimic conditions in a living organism, gene expression could have a profound impact on cell shape,” said Zheng Yin, the paper’s lead author and a postdoctoral fellow at the Department of Systems Medicine and Bioengineering of The Methodist Hospital Research Institute (TMHRI). “This matters because many cancer biologists believe metastasis depends in part on the ability of cells to take on different shapes to escape their confines and spread to healthy tissue. We developed a method of identifying and analyzing the shapes of fruit fly cells, then validated and expanded the discoveries in mammal cancer cells..”The scientists began their study in fruit fly immune cells called hemocytes. Under normal conditions, each hemocyte was found to take on just one of five distinct shapes about 98 percent of the time. In contrast to conventional wisdom, other shapes and “intermediate” forms were rare, suggesting genes that control cell shape behave more like light switches than teakettles coming to a slow boil. Genetic manipulation of these cells in a lab setting supported that view as well.Next the group examined human and mouse melanoma cells, which also take on a variety of forms. The researchers identified seven genes that cause cells to take on an especially rounded form, or else an elongated form. One of these genes, PTEN, had a particularly strong impact. When turned off, virtually all cells became elongated or large and rounded, two shapes that can help cancerous cells escape confinement, travel blood vessels, and infiltrate healthy tissues. …

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