Researchers at the Hospital de Mar Research Institute (IMIM) have discovered that the protein LOXL2 has a function within the cell nucleus thus far unknown. They have also described a new chemical reaction of this protein on histone H3 that would be involved in gene silencing, one of which would be involved in the progression of breast, larynx, lung and skin tumours.
Led by Dr Sandra Peiró, the study is a significant advance in describing the evolution of tumours and opens the door to researching new treatments that block their activity. ‘LOXL2’s action on the intra-cellular level and its interaction with histone H3 stimulates tumour growth. The fact that the protein LOXL2 is an enzyme and is overly expressed in many types of cancer makes it a very good therapeutic target. Now that we know how it acts, we need to keep working to develop chemical inhibitors that counteract its activity’, the researcher explained.
Previous studies had identified the extra-cellular function of the protein LOXL2, and it was being studied as a possible therapeutic target for avoiding metastasis in certain kinds of tumours. However, this study has described the presence of this protein at the level of the cell nucleus for the first time.
The process of gene expression in cells consists of transforming the information of the DNA into the proteins necessary to carry out different functions. The DNA molecule has been found to form a certain structure due to its interaction with some proteins called histones. When these histones are modified, the structure of the DNA is also modified and the final result is the expression or non-expression of a certain group of genes.
In the case of tumour cells, the protein LOXL2 acts upon one of these histones (histone H3) and modifies it, eliminating the lysine 4 amino group, a change never described before. As a result of its action, the genes modulated by histone H3, modified by LOXL2, stop expression, preventing the cells from behaving normally and favouring tumour development.
The work of Sandra Peiró’s team is the conclusion of three years of effort focused on the biochemical characterisation of the protein LOXL2 and the study of its role in the modification of histone H3. Since this modification had never been described before, the data obtained open many lines of research. The location on the genomic level of the protein LOXL2 and histone H3, modified by LOXL2, and the possible existence of some enzyme that might neutralise its function, are two of the questions that the group aims to tackle in the years to come. IMIM (Hospital del Mar Research Institute)

Researchers at National Jewish Health have discovered a novel genetic mechanism of immune deficiency. Magdalena M. Gorska, MD, PhD, and Rafeul Alam, MD, PhD, identified a mutation in Unc119 that causes immunodeficiency known as idiopathic CD4 lymphopenia. Unc119 is a signalling protein that activates and induces T cell proliferation. The mutation impairs Unc119 ability to activate T cells.
‘A better understanding of the molecular mechanisms associated with this mutation will improve diagnosis and pave the way for development of new therapies,’ said Dr. Gorska.
Nearly a decade ago Drs. Alam and Gorska identified Unc119 as a novel activator of SRC-type tyrosine kinases, important regulators of cellular function. Since then, they have published numerous papers where they characterised the function of this protein in various aspects of the immune system.
Idiopathic CD4 lymphopenia is a rare and heterogeneous syndrome defined by low levels of CD4 T cells in the absence of HIV infection, which predisposes patients to infections and malignancies. Recent research by others had linked the syndrome to reduced activation of the SRC-type kinase known as Lck. The latter kinase is involved in T cell development, activation and proliferation.
So, Drs. Alam and Gorska thought Unc119, an activator of Lck, might be involved. They kept an eye out for patients with CD4 lymphopenia coming to National Jewish Health, which specialises in immune-related disorders as well as respiratory and cardiac diseases. They identified three patients with CD4 lymphopenia, then sequenced their Unc119 gene as well as the Unc119 gene in several patients who suffered low CD4 T cell counts as a result of other conditions.
One of the three patients, a 32-year-old woman with a history of recurrent infections, had a missense mutation in her Unc119 gene. The same mutation was not present in other lymphopenia patients nor in any genetic database.
The researchers then performed several studies with the woman’s blood cells, to understand the mutation’s effect. They introduced the mutated gene into normal T cells and examined the outcome.
The mutation prevents Lck activation and its downstream signalling. It also reduces the amount of Lck found near the plasma membrane, where it plays a major role in propagating signals from the T-cell receptor. Proliferation of T cells, which normally occurs on stimulation of T-cell receptors, was profoundly reduced in cells from the patient.
‘Since we originally published our findings earlier this year, we have received inquiries from many physicians with lymphopenia subjects,’ said Dr. Alam. ‘Working with them, we expect to find several more patients with this novel mutation, which should help us better understand its effect, improve diagnosis and possibly find therapies.’
At this point there is no treatment for CD4 lymphopenia caused by this mutation other than close monitoring of the patient and treatment of resulting infections and malignancies. National Jewish Health

In a series of studies Penn researchers demonstrated that, while tests created for AD are effectively diagnosing the condition when it’s clear cut, additional tests are needed to address the many cases with mixed pathology.
‘With the emergence of disease-modifying treatments for AD and other neurodegenerative diseases, it will be of utmost importance to accurately identify the underlying neuropathology in patients,’ said senior author John Q. Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine and co-director of the Center for Neurodegenerative Disease Research at Penn.
In one study, the Penn team compared results of a test looking at levels of tau and amyloid beta (Aß) in the spinal fluid, using two different types of analytical platforms. They determined that values from the two platforms could effectively be transformed into equivalent units, and these values accurately distinguished AD from FTLD. A cutoff of 0.34 for the t-tau:Aß1-42 ratio had 90 – 100 percent sensitivity and 91-96.7 percent specificity to differentiate FTLD cases, respectively.
In another study, the team looked at patient cases with more than one underlying neurodegenerative disease and compared the accuracy of the biomarkers using clinical and neuropathological diagnosis. They determined that cerebral spinal fluid (CSF) Aß and tau assays provided a valid diagnosis of AD but, in mixed pathology cases where Alzheimer’s was present along with other diseases (confirmed by autopsy), the testing strategies classified the diagnosis as AD alone.
‘We need to develop better CSF diagnostic panels for the early diagnosis of neurodegenerative dementias, including those due to mixed neurodegenerative disease pathologies that commonly co-occur with Alzheimer’s,’ said senior author Murray Grossman, MD, professor of Neurology and director of the Penn FTLD Center. Perelman School of Medicine

Dr James Flanagan, a Breast Cancer Campaign scientific fellow in the Department of Surgery and Cancer at Imperial College London, has uncovered the first strong evidence that molecular or ‘epigenetic’ changes in a gene can be associated with breast cancer risk and can be detected many years before breast cancer develops.
The research involved 640 women with breast cancer and 741 controls who enrolled in three previous studies, the earliest of which began in 1992. The researchers analysed blood samples that the women donated on average three years before being diagnosed with breast cancer to find out whether the alteration of single genes by a process called methylation can predict whether women have an increased breast cancer risk.
Dr Flanagan found that the women with the highest level of methylation on one area of a gene called ATM were twice as likely to get breast cancer as women with the lowest level. This result was particularly clear in blood samples taken from women under the age of 60.
Importantly, because this is the first study using blood taken on average three years before diagnosis and in some cases up to eleven years, it shows that the genes were not altered because of active cancer in the body or by treatments for cancer, which has been a problem with previous studies that took blood after diagnosis.
These findings provide strong evidence that looking at this type of epigenetic alteration (methylation) on individual genes could be used as a blood test to help assess breast cancer risk. When used in combination with other risk assessment tools such as genetic testing and risk factor profiling, this simple blood test could identify those at higher risk, helping doctors to monitor and one day maybe even prevent breast cancer ever developing.
The findings now need rigorous testing in many more individuals and many more genes that contribute to a person’s risk profile need to be identified, as this is just one gene that makes up a small component.
Epigenetics research is changing the way scientists think about genes and their development and so could play an important role in helping to prevent cancer. It was previously thought that only errors in the fundamental genetic information from our DNA – whether inherited or caused by environmental factors – determined whether our cells become cancerous. However, new research is showing how chemical modifications to DNA, that control our genes, could be even more important than our DNA alone in determining how our cells grow. Imperial College London

Transposon-mediated insertional mutagenesis accelerates the progression of ductal pancreatic cancer in mice.
In a study researchers have identified a potential new therapeutic target for pancreatic cancer.
The team found that when a gene involved in protein degradation is switched-off through chemical tags on the DNA’s surface, pancreatic cancer cells are protected from the bodies’ natural cell death processes, become more aggressive, and can rapidly spread.
Pancreatic cancer kills around 8,000 people every year in the UK and, although survival rates are gradually improving, fewer than 1 in 5 patients survive for a year or more following their diagnosis.
Co-lead author Professor David Tuveson, from Cancer Research UK’s Cambridge Research Institute, said: ‘The genetics of pancreatic cancer has already been studied in some detail, so we were surprised to find that this gene hadn’t been picked up before. We suspected that the fault wasn’t in the genetic code at all, but in the chemical tags on the surface of the DNA that switch genes on and off, and by running more lab tests we were able to confirm this.’
The team expects this gene, USP9X, could be faulty in up to 15 per cent of pancreatic cancers, raising the prospect that existing drugs, which strip away these chemical tags, could be an effective way of treating some pancreatic cancers.
.’ This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer. ‘
…’Drugs which strip away these tags are already showing promise in lung cancer and this study suggests they could also be effective in treating up to 15 per cent of pancreatic cancers,’ continues Professor Tuveson.
The researchers used a mouse model of pancreatic cancer to screen for genes that speed up pancreatic cancer growth using a technique called ‘Sleeping Beauty transposon mutagenesis’. This system uses mobile genetic elements that hop around the cell’s DNA from one location to the next. Cells that acquire mutations in genes that contribute to cancer development will grow out and ‘driver’ cancer genes may be identified.
By introducing the Sleeping Beauty transposon into mice pre-disposed to develop pancreatic cancer, the researchers were able to screen for a class of genes called a tumour suppressor that, under normal circumstances, would protect against cancer. These genes are a bit like the cell’s ‘brakes’, so when they become faulty there is little to stop the cell from multiplying out of control.
This approach uncovered many genes already linked to pancreatic cancer. But unexpectedly, USP9X, was identified. Wellcome Trust Sanger Institute