St. Jude Children’s Research Hospital scientists led a study showing that mutations in a gene responsible for amyotrophic lateral sclerosis (ALS) disrupt the RNA transport system in nerve cells.
The findings offer a new avenue for researchers to pursue in the quest for desperately needed treatments for ALS, a disorder that kills most patients within five years of diagnosis. ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 individuals nationwide each year and is associated with muscle weakness and paralysis.
The gene, TDP-43, carries instructions for making a protein of the same name. While mutations in TDP-43 were known to cause ALS and a related neurodegenerative disorder, until now the mechanism involved was a mystery. This study showed for the first time that the mutations disrupt efficient movement within nerve cells of RNA molecules. These RNA molecules direct protein assembly based on instructions carried in DNA. Correct transport of these RNAs permits proteins to be made in the right place at the right time.
Working in motor neurons derived from patients with ALS, researchers demonstrated that each of three different TDP-43 mutations impaired delivery of RNA molecules to their final destination near the junction where a nerve and its target muscle meet. Without the RNA molecules, nerves cannot make proteins necessary to function normally and respond quickly when stimulated. Motor neurons govern movement, including breathing. Their death and deterioration is a hallmark of ALS.
The results also provide insight into how problems in RNA metabolism, including disturbances in RNA regulation and functioning, lead to ALS and other neurodegenerative diseases.
‘Five years of tremendous progress in ALS genetics has revealed that RNA metabolism is a critical pathway that is impaired in this disease,’ said the study’s corresponding author J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. ‘But RNA metabolism is a complex process that involves multiple steps that are carried out in different parts of the cell. This study provides a more refined understanding of how ALS-causing mutations impair RNA metabolism so we know what needs fixing therapeutically.’
TDP-43 belongs to a family of proteins that bind to RNA and regulate its function. Normally TDP-43 is stored in the cell’s command center, the nucleus. There the protein prepares DNA for translation into the proteins that do the work of cells and shuttles the resulting RNA, called mRNA, from the nucleus to the cytoplasm, the cell’s liquid center. While clumps of TDP-43 were known to accumulate in the cytoplasm of the motor neurons of patients with ALS and other neurodegenerative diseases, the protein’s function there was unknown.
This study provides an answer. The work was done in motor neurons from the fruit fly Drosophila melanogaster, mouse brain cells and human motor neurons produced by reprogramming cells from ALS patients with three different TDP-43 mutations. Co-first author Nael Alami, Ph.D., a postdoctoral fellow in Taylor’s laboratory, developed a florescent RNA beacon that let investigators track movement of RNA molecules in living cells.
Researchers demonstrated that TDP-43 is part of a molecule called an RNA transport granule. These granules are responsible for moving mRNA efficiently to the end of the axon where the molecule is translated into a protein. For this study, scientists used Neurofilament-L (NEFL) mRNA, which is known to bind TDP-43.
In human motor neurons growing in the laboratory, investigators found that transport granules with mutant TDP-43 were more likely than granules with unaltered TDP-43 to stall en route to the nerve ending and sometimes reverse direction. The defect in the human ALS motor neurons was apparent after the first week.
Evidence from mice suggests TDP-43 mutations selectively rather than globally disrupt movement in nerve cells. The mutations did not affect movement of another cell structure, the mitochondria, along the axon where mRNA movement was impaired.
‘We know neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases, seem to share a common mechanism,’ Alami said. ‘We plan to use our finding from this study to look for similar defects in those diseases.’
St. Jude Children’s Research Hospital
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A new technology developed by Harvard Medical School researchers at the Massachusetts General Hospital Center for Systems Biology allows the simultaneous analysis of hundreds of cancer-related protein markers from minuscule patient samples gathered through minimally invasive methods. This powerful and sensitive technology uses antibodies linked to unique DNA ‘barcodes’ to detect a wide range of target proteins.
It could serve as a tool to help clinicians gain insights into the biology of cancer progression as well as determine why certain cancer therapies stop working or are ineffective to begin with.
Minimally invasive techniques—such as fine-needle aspiration or circulating tumour cell analysis—are increasingly employed to track treatment response over time in clinical trials, as the tests can be simple and cheap to perform. Fine-needle aspirates are also much less invasive than core biopsies or surgical biopsies, since very small needles are used. The challenge has been to comprehensively analyse the very few cells that are obtained via this method.
‘What this study sought to achieve was to vastly expand the information that we can obtain from just a few cells,’ explained Cesar Castro, HMS instructor in medicine at Mass General and a co-author of the paper. ‘Instead of trying to procure more tissue to study, we shrank the analysis process so that it could now be performed on a few cells.’
Until now, pathologists have been able to examine only a handful of protein markers at a time for tumour analyses. With this new technology, the researchers have demonstrated the ability to look at hundreds of markers simultaneously, down to the single-cell level.
‘We are no longer limited by the scant cell quantities procured through minimally invasive procedures,’ Castro said. ‘Rather, the bottleneck will now be our own understanding of the various pathways involved in disease progression and drug target modulation.’
The new method uses an approach known as DNA-barcoded antibody sensing, in which unique DNA sequences are attached to antibodies against known cancer marker proteins. The DNA ‘barcodes’ are linked to the antibodies with a special type of glue that breaks apart when exposed to light. When mixed with a tumour sample, the antibodies seek out and bind to their targets; then a light pulse releases the unique DNA barcodes of these bound antibodies that are subsequently tagged with fluorescently labelled complementary barcodes. The tagged barcodes can be detected and quantified via imaging, revealing which markers are present in the sample.
After initially demonstrating and validating the technique’s feasibility in cell lines and single cells, the team tested it on samples from patients with lung cancer. The technology was able to reflect the great heterogeneity—differences in features such as cell-surface protein expression—of cells within a single tumour and to reveal significant differences in protein expression between tumours that appeared identical under the microscope. Examination of cells taken at various time points from participants in a clinical trial of a targeted therapy drug revealed patterns that distinguished those who did and did not respond to treatment.
‘We showed that this technology works well beyond the highly regulated laboratory environment, extending into early-phase clinical trials,’ said Castro, who is also a medical oncologist in the Mass General Cancer Center and director of the Cancer Program within the hospital’s Center for Systems Biology. ‘In this era of personalised medicine, we could leverage such technology not only to monitor but actually to predict treatment response. By obtaining samples from patients before initiating therapy and then exposing them to different chemo-therapeutics or targeted therapies, we could select the most appropriate therapy for individual patients.’
Harvard Medical School
The once sketchy landscape of the molecular defects behind bladder cancer now resembles a road map to new, targeted treatments thanks to the unified efforts of scientists and physicians at 40 institutions.
Deep molecular analysis of 131 muscle-invasive bladder cancer tumours found recurring defects in 32 genes for the cancer that currently has no targeted therapies.
‘By dramatically increasing our knowledge of the molecular basis of bladder cancers, this project casts a spotlight on particular molecules and biological pathways that may serve as targets for a more individualised approach to therapy,’ said project co-chair, lead and senior author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center in Houston.
‘While many of these genomic alterations have been tied to other cancers, nine of these genes have never been reported as significantly mutated in any other type of malignancy,’ Weinstein said. ‘These findings mark additional progress away from defining cancer by organ site and toward molecular classification that spans tumour types.’
Basis for investigating novel therapies and new uses of existing drugs
The most common bladder cancer, urothelial carcinoma, will kill an estimated 15,000 Americans in 2014, with 10 times as many deaths worldwide. Muscle-invasive disease is the most lethal form. Current treatment includes surgery, cisplatin-based multi-agent chemotherapy and radiation.
‘These TCGA data provide a perfect storm for advancing treatment for muscle invasive and hard-to-treat cancer,’ said project co-leader and co-senior author Seth P. Lerner, M.D., professor and chair of Urologic Oncology and Bladder Cancer program leader at Baylor College of Medicine in Houston.
‘We found potential therapeutic targets in 69 percent of tumours and identified bladder cancer subtypes based on gene mutation and expression data,’ Lerner said. ‘One subtype looks similar to squamous cell cancer of the head, neck and lung and basal-like breast cancer. Another subtype looks similar to luminal A breast cancer. These genomic similarities create a logical path to test targeted therapies from these other subtypes of cancer rather than treating bladder cancers as one disease.’
Lerner said long-term planning for clinical trials based on the TCGA data has begun in earnest and will continue this week during the 2014 Genitourinary Cancers Symposium in San Francisco.
Researchers analysed tumours for genetic mutations, gene copy number (deletions and amplifications), gene expression of messenger RNA, microRNA and protein expression, among other factors.
Two biological pathways provided the most common therapeutic targets, including molecules addressed by drugs in clinical trials or approved for other types of cancer.
45 percent of tumours had targets in the growth-factor-signalling receptor tyrosine kinase/MAPK pathway, including HER2 – best known as a drug target in about one third of breast cancers – in 15 percent of tumours, EGFR in 9 percent and FGFR3 in 17 percent.
42 percent had targets in the PI3K/AKT/mTOR pathway, including PIK3CA, which occurred in 17 percent of tumours, TSC1 or TSC2 in 9 percent and AKT3 in 10 percent of tumours. PI3K inhibitors are under development and mTOR inhibitors have been approved for select cancers.
A striking new finding, Weinstein said, was of frequent alterations in genes involved with the regulation of chromatin, the combination of DNA and histone proteins that makes up chromosomes.
Chromatin remodelling greatly influences gene expression and the team found alterations in this pathway in 89 percent of tumours, more than in any other type of cancer analysed to date. This makes bladder cancer a prime candidate for a new class of drugs under development, the authors noted.
Viral DNA was found in 6 percent of tumours, suggesting that viral infection might play a role in the development of a small percentage of bladder cancers.
M D Anderson Cancer Center
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Bioengineers at Rice University and the University of Texas Medical Branch (UTMB) at Galveston have developed a simple, highly sensitive and efficient test for the diarrhoeal disease cryptosporidiosis that could have great impact on global health.
Results from the diagnostic developed by the lab of Rice bioengineer Rebecca Richards-Kortum are read from a paper strip that resembles a pregnancy test. Lines on the strip tell whether samples taken from the stool of a patient contain genetic DNA from the parasite that causes the disease.
‘Diarrhoeal illness is a leading cause of global mortality and morbidity,’ said Richards-Kortum, director of the Rice 360˚: Institute for Global Health Technologies. ‘Parasites such as cryptosporidium are more common causes of prolonged diarrhoea. Current laboratory tests are not sensitive, are time-consuming and require days before results are available. A rapid, affordable, accurate point-of-care test could greatly enhance care for the underserved populations who are most affected by parasites that cause diarrhoeal illness.’
A. Clinton White, director of the Infectious Disease Division at UTMB, asked Richards-Kortum to help develop a diagnostic test for the parasite. ‘I’ve been working with cryptosporidium for more than 20 years, so I wanted to combine her expertise in diagnosis with our clinical interest,’ he said. ‘Recent studies in Africa and South Asia by people using sophisticated techniques show this organism is a very common, under-appreciated cause of diarrhoeal disease in under-resourced countries.’
Current specialized tests that depend on microscopic or fluorescent analysis of stool samples or polymerase chain reactions (PCR) that amplify pathogen DNA are considered impractical for deployment in developing countries because of the need for expensive equipment and/or the electricity to operate it.
The Rice test depends on recent developments in a recombinase polymerase amplification (RPA) technique that gives similar ‘gold standard’ results to PCR but operates between room and body temperatures. In Rice’s experiments, samples were prepared with a commercial chemical kit that releases all the DNA and RNA in the small amount of stool tested. The purified nucleic acids are then combined with RPA primers and enzymes tuned to amplify the pathogen of interest, Crannell said.
‘If the pathogen DNA is present, these primers will amplify it billions of times to a level that we can easily detect,’ he said. The sample is then flowed over the detection strip, which provides a positive or negative result.
The RPA enzymes are stable in their dried form and can be safely stored at the point of care without refrigeration for up to a year, he said.
While current tests might catch the disease in samples with thousands of the pathogens, the Rice technique detects the presence of very few – even one – parasite in a sample. In their experiments, the researchers reported the presence or absence of the disease was correctly identified in 27 of 28 infected and control-group mice and all 21 humans whose stool was tested.
Rice University
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New research from Queen Mary University of London has identified a novel genetic defect among patients with bone marrow failure, which could reveal its underlying cause.
The study detected and identified a new disease gene (ERCC6L2). In its normal form, the gene plays a key role in protecting DNA from damaging agents, but when the gene is mutated the cell is not able to protect itself in the normal way.
The research findings suggest that the gene defect and the subsequent DNA damage was the underlying cause of bone marrow failure among the study participants.
Bone marrow failure is a term used for a group of life threatening disorders associated with an inability of the bone marrow to make an adequate number of mature blood cells.
Patients were recruited from all over the world to join an international bone marrow failure registry and researchers used new DNA sequencing technologies to study cases of bone marrow failure with similar clinical features. These included bone marrow failure associated with neurological abnormalities (learning defects and developmental delay), and patients whose parents were first cousins.
The findings mean it is now possible to carry out a reliable genetic test (including antenatal testing) in these families and get an accurate diagnosis. In the long term, with further research, the findings could lead to the development of new treatment for this specific gene defect.
Professor Inderjeet Dokal, Chair of Paediatrics and Child Health at Queen Mary University of London, comments: ‘New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure. This is a promising finding which we hope one day could lead to finding an effective treatment for this type of gene defect. Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.
‘Now we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure.’
Queen Mary University
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Scientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.
Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behaviour measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioural measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.
A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.
‘The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder,’ Bearden said. ‘This is an innovative approach to identifying genetically influenced brain and behavioural measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are.’
‘These findings are really just the first step in getting us a little closer to the roots of bipolar disorder,’ Bearden said. ‘What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field.’
The individuals assessed in this study are members of large families living in Costa Rica’s central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations.
UCLA Health System
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People who are dementia-free but have two parents with Alzheimer’s disease may show signs of the disease on brain scans decades before symptoms appear, according to a new study. ‘Studies show that by the time people come in for a diagnosis, there may be a large amount of irreversible brain damage already present,’ said study author Lisa Mosconi, PhD, with the New York University School of Medicine in New York. ‘This is why it is ideal that we find signs of the disease in high-risk people before symptoms occur.’ For the study, 52 people between the ages of 32 and 72 and free of dementia underwent several kinds of brain scans, including Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) scans. PET scans measure the amount of brain plaques as well as overall brain activity, such as brain metabolism. MRI scans look at brain structure and possible reductions in brain volume. Participants were split into four groups of 13 people: those with a mother with Alzheimer’s disease, a father, both parents, or no family history of the disease. People with both parents who had Alzheimer’s disease showed more severe abnormalities in brain volume, metabolism and five to 10 percent increased brain plaques in certain brain regions compared to the other three groups. ‘Our study also suggests that there might be genes that predispose individuals to develop brain Alzheimer’s pathology as a function of whether one parent or both parents have the disease,’ Mosconi said. ‘We do not yet know which genes, if any, are responsible for these early changes, and we hope that our study will be helpful to future genetic investigations.’ People whose mother had Alzheimer’s disease showed a greater level of the Alzheimer’s disease biomarkers in the brain than people whose father had the disease, which is consistent with previous studies showing that people whose mothers had the disease were more likely to develop it than those with fathers with the disease, Mosconi said. She noted the small sample size of the study. The research was supported by the National Institutes of Health and the Alzheimer’s Association.
American Academy of Neurology
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For the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study may help scientists understand biological mechanisms behind some forms of intellectual impairment.
The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.
An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.
Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: ‘We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.’
She adds: ‘It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.’
The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.
To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.
The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.
Paper reference: Desrivières, S. et al. ‘Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents’ published in Molecular Psychiatry
King’s College London
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Findings show how a genetic mutation in untreated patients is linked to aggressive cancer later in life. It was previously thought that the mutation only occurred in response to therapy.
The research highlights why relapses could occur in some men following hormone therapy. And it could help identify those patients that will develop fatal prostate cancer much earlier for life-extending therapy.
Prostate cancer is the most common cancer in men in the UK, with more than 40,000 new cases diagnosed every year. Treatment options for patients diagnosed with early stage prostate cancer vary from ‘watchful waiting’ to hormone-withdrawal therapy, radiotherapy or surgery.
Additional tests for indicators of aggressive cancer are necessary to help categorise patients so that those with a low-risk of the disease spreading can avoid unnecessary treatment, and those diagnosed with a high-risk can be targeted for more aggressive first line therapy.
Hormone-withdrawal therapy often results in a dramatic remission, however the disease invariably relapses with a resistant form of the cancer. A third of these are due to an increase in copy number of a particular gene called the ‘androgen receptor’. The gene is on the X-Chromosome and so there is normally only one copy of this gene present in men. Prostate cancer thrives on male hormones, and one way that they develop to grow better is to increase the number of copies of the androgen receptor gene. This also enables the cancer to resist therapy.
Lead researchers Dr Jeremy Clark and Prof Colin Cooper from UEA’s school of Biological Sciences carried out the research at the Institute of Cancer Research, London, and at UEA.
Dr Clark said: ‘By the age of 60, the majority of men will have signs of prostate cancer. However, only a small proportion of men will die of the disease. The question is – which of these cancers are dangerous and which are not? Deciding which cancers are going to progress and kill the patient is key to effective patient treatment.’
‘Prostate cancer thrives on male hormones, and cutting the supply of hormones to the cancer is a main avenue of therapy. Prostate cancer only kills the patient when it becomes immune to these therapies. A third of these killer cancers are immune to therapy because they have boosted the number of male hormone receptor (AR) genes in their DNA. This gene boosting, also known as amplification, has been thought to be a response of the tumour to the hormone reduction therapy itself.
‘Our research has shown that an early form of this hormone-gene boosting is present in a number of prostate cancers that have never been treated with hormone reduction therapy. We think that it is these cancers that will grow and kill the patient.
‘This discovery can be used to identify these killer cancers in patients much earlier than is currently possible. Patients could then be selected for more aggressive therapy before the cancer has developed full immunity.’
The research team looked at biomarkers from almost 600 patients prior to hormone-withdrawal therapy. But the method of identification used was labour intensive and time consuming. Developing ways of identifying patients for early therapeutic intervention will be key to implementing this discovery in the clinic. The research team are currently looking at more rapid ways of identifying patients that will develop aggressive cancer.
University of East Anglia
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Cancer researchers led by stem cell scientist Dr. John Dick have discovered a pre-leukemic stem cell that may be the first step in initiating disease and also the culprit that evades therapy and triggers relapse in patients with acute myeloid leukaemia (AML).
The research is a significant leap in understanding the steps that a normal cell has to go through as it turns into AML, says Dr. Dick, and sets the stage to advance personalised cancer medicine by potentially identifying individuals who might benefit from targeting the pre-leukemic stem cell. AML is an aggressive blood cancer that the new research shows starts in stem cells in the bone marrow. Dr. Dick, a Senior Scientist at Princess Margaret Cancer Centre, University Health Network (UHN), and Professor in the Department of Molecular Genetics, University of Toronto, pioneered the cancer stem cell field by first identifying leukaemia stem cells (1994) and colon cancer stem cells (2007).
‘Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage when it may be more amenable to treatment,’ says Dr. Dick, who holds a Canada Research Chair in Stem Cell Biology and is also Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research (OICR).
‘Now we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse,’ he says.
The findings show that in about 25% of AML patients, a mutation in the gene DNMT3a causes pre-leukemic stem cells to develop that function like normal blood stem cells but grow abnormally. These cells survive chemotherapy and can be found in the bone marrow at remission, forming a reservoir of cells that may eventually acquire additional mutations, leading to relapse.
The discovery of pre-leukemic stem cells came out of a large Leukemia Disease Team that Dr. Dick assembled and included oncologists who collected samples for the Princess Margaret Cancer Centre Biobank and genome scientists at the OICR who developed sophisticated targeted sequencing methodology. With this team, it was possible to carry out genomic analysis of more than 100 leukaemia genes on many patient samples. The findings also capitalised on data from more than six years of experiments in Dr. Dick’s lab involving growing human AML in special mice that do not reject human cells.
‘By peering into the black box of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding. People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells. Our study suggests that in some cases the chemotherapy does, in fact, eradicate AML; what it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and ultimately disease relapse,’ says Dr. Dick, who anticipates the findings will spawn accelerated drug development to specifically target DNMT3a.
These findings should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations and even in non-blood cancers.
Princess Margaret Cancer Centre, University Health Network
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Mechanism discovered for how amyotrophic lateral sclerosis mutations damage nerve function
, /in E-News /by 3wmediaSt. Jude Children’s Research Hospital scientists led a study showing that mutations in a gene responsible for amyotrophic lateral sclerosis (ALS) disrupt the RNA transport system in nerve cells.
The findings offer a new avenue for researchers to pursue in the quest for desperately needed treatments for ALS, a disorder that kills most patients within five years of diagnosis. ALS, also known as Lou Gehrig’s disease, is diagnosed in about 5,600 individuals nationwide each year and is associated with muscle weakness and paralysis.
The gene, TDP-43, carries instructions for making a protein of the same name. While mutations in TDP-43 were known to cause ALS and a related neurodegenerative disorder, until now the mechanism involved was a mystery. This study showed for the first time that the mutations disrupt efficient movement within nerve cells of RNA molecules. These RNA molecules direct protein assembly based on instructions carried in DNA. Correct transport of these RNAs permits proteins to be made in the right place at the right time.
Working in motor neurons derived from patients with ALS, researchers demonstrated that each of three different TDP-43 mutations impaired delivery of RNA molecules to their final destination near the junction where a nerve and its target muscle meet. Without the RNA molecules, nerves cannot make proteins necessary to function normally and respond quickly when stimulated. Motor neurons govern movement, including breathing. Their death and deterioration is a hallmark of ALS.
The results also provide insight into how problems in RNA metabolism, including disturbances in RNA regulation and functioning, lead to ALS and other neurodegenerative diseases.
‘Five years of tremendous progress in ALS genetics has revealed that RNA metabolism is a critical pathway that is impaired in this disease,’ said the study’s corresponding author J. Paul Taylor, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. ‘But RNA metabolism is a complex process that involves multiple steps that are carried out in different parts of the cell. This study provides a more refined understanding of how ALS-causing mutations impair RNA metabolism so we know what needs fixing therapeutically.’
TDP-43 belongs to a family of proteins that bind to RNA and regulate its function. Normally TDP-43 is stored in the cell’s command center, the nucleus. There the protein prepares DNA for translation into the proteins that do the work of cells and shuttles the resulting RNA, called mRNA, from the nucleus to the cytoplasm, the cell’s liquid center. While clumps of TDP-43 were known to accumulate in the cytoplasm of the motor neurons of patients with ALS and other neurodegenerative diseases, the protein’s function there was unknown.
This study provides an answer. The work was done in motor neurons from the fruit fly Drosophila melanogaster, mouse brain cells and human motor neurons produced by reprogramming cells from ALS patients with three different TDP-43 mutations. Co-first author Nael Alami, Ph.D., a postdoctoral fellow in Taylor’s laboratory, developed a florescent RNA beacon that let investigators track movement of RNA molecules in living cells.
Researchers demonstrated that TDP-43 is part of a molecule called an RNA transport granule. These granules are responsible for moving mRNA efficiently to the end of the axon where the molecule is translated into a protein. For this study, scientists used Neurofilament-L (NEFL) mRNA, which is known to bind TDP-43.
In human motor neurons growing in the laboratory, investigators found that transport granules with mutant TDP-43 were more likely than granules with unaltered TDP-43 to stall en route to the nerve ending and sometimes reverse direction. The defect in the human ALS motor neurons was apparent after the first week.
Evidence from mice suggests TDP-43 mutations selectively rather than globally disrupt movement in nerve cells. The mutations did not affect movement of another cell structure, the mitochondria, along the axon where mRNA movement was impaired.
‘We know neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases, seem to share a common mechanism,’ Alami said. ‘We plan to use our finding from this study to look for similar defects in those diseases.’ St. Jude Children’s Research Hospital
‘Barcode’ profiling
, /in E-News /by 3wmediaA new technology developed by Harvard Medical School researchers at the Massachusetts General Hospital Center for Systems Biology allows the simultaneous analysis of hundreds of cancer-related protein markers from minuscule patient samples gathered through minimally invasive methods. This powerful and sensitive technology uses antibodies linked to unique DNA ‘barcodes’ to detect a wide range of target proteins.
It could serve as a tool to help clinicians gain insights into the biology of cancer progression as well as determine why certain cancer therapies stop working or are ineffective to begin with.
Minimally invasive techniques—such as fine-needle aspiration or circulating tumour cell analysis—are increasingly employed to track treatment response over time in clinical trials, as the tests can be simple and cheap to perform. Fine-needle aspirates are also much less invasive than core biopsies or surgical biopsies, since very small needles are used. The challenge has been to comprehensively analyse the very few cells that are obtained via this method.
‘What this study sought to achieve was to vastly expand the information that we can obtain from just a few cells,’ explained Cesar Castro, HMS instructor in medicine at Mass General and a co-author of the paper. ‘Instead of trying to procure more tissue to study, we shrank the analysis process so that it could now be performed on a few cells.’
Until now, pathologists have been able to examine only a handful of protein markers at a time for tumour analyses. With this new technology, the researchers have demonstrated the ability to look at hundreds of markers simultaneously, down to the single-cell level.
‘We are no longer limited by the scant cell quantities procured through minimally invasive procedures,’ Castro said. ‘Rather, the bottleneck will now be our own understanding of the various pathways involved in disease progression and drug target modulation.’
The new method uses an approach known as DNA-barcoded antibody sensing, in which unique DNA sequences are attached to antibodies against known cancer marker proteins. The DNA ‘barcodes’ are linked to the antibodies with a special type of glue that breaks apart when exposed to light. When mixed with a tumour sample, the antibodies seek out and bind to their targets; then a light pulse releases the unique DNA barcodes of these bound antibodies that are subsequently tagged with fluorescently labelled complementary barcodes. The tagged barcodes can be detected and quantified via imaging, revealing which markers are present in the sample.
After initially demonstrating and validating the technique’s feasibility in cell lines and single cells, the team tested it on samples from patients with lung cancer. The technology was able to reflect the great heterogeneity—differences in features such as cell-surface protein expression—of cells within a single tumour and to reveal significant differences in protein expression between tumours that appeared identical under the microscope. Examination of cells taken at various time points from participants in a clinical trial of a targeted therapy drug revealed patterns that distinguished those who did and did not respond to treatment.
‘We showed that this technology works well beyond the highly regulated laboratory environment, extending into early-phase clinical trials,’ said Castro, who is also a medical oncologist in the Mass General Cancer Center and director of the Cancer Program within the hospital’s Center for Systems Biology. ‘In this era of personalised medicine, we could leverage such technology not only to monitor but actually to predict treatment response. By obtaining samples from patients before initiating therapy and then exposing them to different chemo-therapeutics or targeted therapies, we could select the most appropriate therapy for individual patients.’ Harvard Medical School
Study uncovers molecular keys to invasive bladder cancer
, /in E-News /by 3wmediaThe once sketchy landscape of the molecular defects behind bladder cancer now resembles a road map to new, targeted treatments thanks to the unified efforts of scientists and physicians at 40 institutions.
Deep molecular analysis of 131 muscle-invasive bladder cancer tumours found recurring defects in 32 genes for the cancer that currently has no targeted therapies.
‘By dramatically increasing our knowledge of the molecular basis of bladder cancers, this project casts a spotlight on particular molecules and biological pathways that may serve as targets for a more individualised approach to therapy,’ said project co-chair, lead and senior author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center in Houston.
‘While many of these genomic alterations have been tied to other cancers, nine of these genes have never been reported as significantly mutated in any other type of malignancy,’ Weinstein said. ‘These findings mark additional progress away from defining cancer by organ site and toward molecular classification that spans tumour types.’
Basis for investigating novel therapies and new uses of existing drugs
The most common bladder cancer, urothelial carcinoma, will kill an estimated 15,000 Americans in 2014, with 10 times as many deaths worldwide. Muscle-invasive disease is the most lethal form. Current treatment includes surgery, cisplatin-based multi-agent chemotherapy and radiation.
‘These TCGA data provide a perfect storm for advancing treatment for muscle invasive and hard-to-treat cancer,’ said project co-leader and co-senior author Seth P. Lerner, M.D., professor and chair of Urologic Oncology and Bladder Cancer program leader at Baylor College of Medicine in Houston.
‘We found potential therapeutic targets in 69 percent of tumours and identified bladder cancer subtypes based on gene mutation and expression data,’ Lerner said. ‘One subtype looks similar to squamous cell cancer of the head, neck and lung and basal-like breast cancer. Another subtype looks similar to luminal A breast cancer. These genomic similarities create a logical path to test targeted therapies from these other subtypes of cancer rather than treating bladder cancers as one disease.’
Lerner said long-term planning for clinical trials based on the TCGA data has begun in earnest and will continue this week during the 2014 Genitourinary Cancers Symposium in San Francisco.
Researchers analysed tumours for genetic mutations, gene copy number (deletions and amplifications), gene expression of messenger RNA, microRNA and protein expression, among other factors.
Two biological pathways provided the most common therapeutic targets, including molecules addressed by drugs in clinical trials or approved for other types of cancer.
45 percent of tumours had targets in the growth-factor-signalling receptor tyrosine kinase/MAPK pathway, including HER2 – best known as a drug target in about one third of breast cancers – in 15 percent of tumours, EGFR in 9 percent and FGFR3 in 17 percent.
42 percent had targets in the PI3K/AKT/mTOR pathway, including PIK3CA, which occurred in 17 percent of tumours, TSC1 or TSC2 in 9 percent and AKT3 in 10 percent of tumours. PI3K inhibitors are under development and mTOR inhibitors have been approved for select cancers.
A striking new finding, Weinstein said, was of frequent alterations in genes involved with the regulation of chromatin, the combination of DNA and histone proteins that makes up chromosomes.
Chromatin remodelling greatly influences gene expression and the team found alterations in this pathway in 89 percent of tumours, more than in any other type of cancer analysed to date. This makes bladder cancer a prime candidate for a new class of drugs under development, the authors noted.
Viral DNA was found in 6 percent of tumours, suggesting that viral infection might play a role in the development of a small percentage of bladder cancers. M D Anderson Cancer Center
Quick test finds signs of diarrhoeal disease
, /in E-News /by 3wmediaBioengineers at Rice University and the University of Texas Medical Branch (UTMB) at Galveston have developed a simple, highly sensitive and efficient test for the diarrhoeal disease cryptosporidiosis that could have great impact on global health.
Results from the diagnostic developed by the lab of Rice bioengineer Rebecca Richards-Kortum are read from a paper strip that resembles a pregnancy test. Lines on the strip tell whether samples taken from the stool of a patient contain genetic DNA from the parasite that causes the disease.
‘Diarrhoeal illness is a leading cause of global mortality and morbidity,’ said Richards-Kortum, director of the Rice 360˚: Institute for Global Health Technologies. ‘Parasites such as cryptosporidium are more common causes of prolonged diarrhoea. Current laboratory tests are not sensitive, are time-consuming and require days before results are available. A rapid, affordable, accurate point-of-care test could greatly enhance care for the underserved populations who are most affected by parasites that cause diarrhoeal illness.’
A. Clinton White, director of the Infectious Disease Division at UTMB, asked Richards-Kortum to help develop a diagnostic test for the parasite. ‘I’ve been working with cryptosporidium for more than 20 years, so I wanted to combine her expertise in diagnosis with our clinical interest,’ he said. ‘Recent studies in Africa and South Asia by people using sophisticated techniques show this organism is a very common, under-appreciated cause of diarrhoeal disease in under-resourced countries.’
Current specialized tests that depend on microscopic or fluorescent analysis of stool samples or polymerase chain reactions (PCR) that amplify pathogen DNA are considered impractical for deployment in developing countries because of the need for expensive equipment and/or the electricity to operate it.
The Rice test depends on recent developments in a recombinase polymerase amplification (RPA) technique that gives similar ‘gold standard’ results to PCR but operates between room and body temperatures. In Rice’s experiments, samples were prepared with a commercial chemical kit that releases all the DNA and RNA in the small amount of stool tested. The purified nucleic acids are then combined with RPA primers and enzymes tuned to amplify the pathogen of interest, Crannell said.
‘If the pathogen DNA is present, these primers will amplify it billions of times to a level that we can easily detect,’ he said. The sample is then flowed over the detection strip, which provides a positive or negative result.
The RPA enzymes are stable in their dried form and can be safely stored at the point of care without refrigeration for up to a year, he said.
While current tests might catch the disease in samples with thousands of the pathogens, the Rice technique detects the presence of very few – even one – parasite in a sample. In their experiments, the researchers reported the presence or absence of the disease was correctly identified in 27 of 28 infected and control-group mice and all 21 humans whose stool was tested. Rice University
New disease gene discovery sheds light on cause of bone marrow failure
, /in E-News /by 3wmediaNew research from Queen Mary University of London has identified a novel genetic defect among patients with bone marrow failure, which could reveal its underlying cause.
The study detected and identified a new disease gene (ERCC6L2). In its normal form, the gene plays a key role in protecting DNA from damaging agents, but when the gene is mutated the cell is not able to protect itself in the normal way.
The research findings suggest that the gene defect and the subsequent DNA damage was the underlying cause of bone marrow failure among the study participants.
Bone marrow failure is a term used for a group of life threatening disorders associated with an inability of the bone marrow to make an adequate number of mature blood cells.
Patients were recruited from all over the world to join an international bone marrow failure registry and researchers used new DNA sequencing technologies to study cases of bone marrow failure with similar clinical features. These included bone marrow failure associated with neurological abnormalities (learning defects and developmental delay), and patients whose parents were first cousins.
The findings mean it is now possible to carry out a reliable genetic test (including antenatal testing) in these families and get an accurate diagnosis. In the long term, with further research, the findings could lead to the development of new treatment for this specific gene defect.
Professor Inderjeet Dokal, Chair of Paediatrics and Child Health at Queen Mary University of London, comments: ‘New DNA sequencing technology has enabled us to identify and define a new gene defect which causes a particular type of bone marrow failure. This is a promising finding which we hope one day could lead to finding an effective treatment for this type of gene defect. Clinicians treating patients with bone marrow failure should now include analysis for this gene in their investigation.
‘Now we know this research technique works, we plan to carry out further studies to shed more light on the genetic basis of many other cases of bone marrow failure.’ Queen Mary University
Understanding the basic biology of bipolar disorder
, /in E-News /by 3wmediaScientists know there is a strong genetic component to bipolar disorder, but they have had an extremely difficult time identifying the genes that cause it. So, in an effort to better understand the illness’s genetic causes, researchers at UCLA tried a new approach.
Instead of only using a standard clinical interview to determine whether individuals met the criteria for a clinical diagnosis of bipolar disorder, the researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behaviour measures. Using the new method, UCLA investigators — working with collaborators from UC San Francisco, Colombia’s University of Antioquia and the University of Costa Rica — identified about 50 brain and behavioural measures that are both under strong genetic control and associated with bipolar disorder. Their discoveries could be a major step toward identifying the specific genes that contribute to the illness.
A severe mental illness that affects about 1 to 2 percent of the population, bipolar disorder causes unusual shifts in mood and energy, and it interferes with the ability to carry out everyday tasks. Those with the disorder can experience tremendous highs and extreme lows — to the point of not wanting to get out of bed when they’re feeling down. The genetic causes of bipolar disorder are highly complex and likely involve many different genes, said Carrie Bearden, a senior author of the study and an associate professor of psychiatry and psychology at the UCLA Semel Institute for Neuroscience and Human Behavior.
‘The field of psychiatric genetics has long struggled to find an effective approach to begin dissecting the genetic basis of bipolar disorder,’ Bearden said. ‘This is an innovative approach to identifying genetically influenced brain and behavioural measures that are more closely tied to the underlying biology of bipolar disorder than the clinical symptoms alone are.’
‘These findings are really just the first step in getting us a little closer to the roots of bipolar disorder,’ Bearden said. ‘What was really exciting about this project was that we were able to collect the most extensive set of traits associated with bipolar disorder ever assessed within any study sample. These data will be a really valuable resource for the field.’
The individuals assessed in this study are members of large families living in Costa Rica’s central valley and Antioquia, Colombia. The families were founded by European and native Amerindian populations about 400 years ago and have a very high incidence of bipolar disorder. The groups were chosen because they have remained fairly isolated since their founding and their genetics are therefore simpler for scientists to study than those of general populations. UCLA Health System
Two parents with Alzheimer’s Disease? Disease may show up decades early on brain scans
, /in E-News /by 3wmediaPeople who are dementia-free but have two parents with Alzheimer’s disease may show signs of the disease on brain scans decades before symptoms appear, according to a new study. ‘Studies show that by the time people come in for a diagnosis, there may be a large amount of irreversible brain damage already present,’ said study author Lisa Mosconi, PhD, with the New York University School of Medicine in New York. ‘This is why it is ideal that we find signs of the disease in high-risk people before symptoms occur.’ For the study, 52 people between the ages of 32 and 72 and free of dementia underwent several kinds of brain scans, including Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) scans. PET scans measure the amount of brain plaques as well as overall brain activity, such as brain metabolism. MRI scans look at brain structure and possible reductions in brain volume. Participants were split into four groups of 13 people: those with a mother with Alzheimer’s disease, a father, both parents, or no family history of the disease. People with both parents who had Alzheimer’s disease showed more severe abnormalities in brain volume, metabolism and five to 10 percent increased brain plaques in certain brain regions compared to the other three groups. ‘Our study also suggests that there might be genes that predispose individuals to develop brain Alzheimer’s pathology as a function of whether one parent or both parents have the disease,’ Mosconi said. ‘We do not yet know which genes, if any, are responsible for these early changes, and we hope that our study will be helpful to future genetic investigations.’ People whose mother had Alzheimer’s disease showed a greater level of the Alzheimer’s disease biomarkers in the brain than people whose father had the disease, which is consistent with previous studies showing that people whose mothers had the disease were more likely to develop it than those with fathers with the disease, Mosconi said. She noted the small sample size of the study. The research was supported by the National Institutes of Health and the Alzheimer’s Association. American Academy of Neurology
Scientists identify gene linking brain structure to intelligence
, /in E-News /by 3wmediaFor the first time, scientists at King’s College London have identified a gene linking the thickness of the grey matter in the brain to intelligence. The study may help scientists understand biological mechanisms behind some forms of intellectual impairment.
The researchers looked at the cerebral cortex, the outermost layer of the human brain. It is known as ‘grey matter’ and plays a key role in memory, attention, perceptual awareness, thought, language and consciousness. Previous studies have shown that the thickness of the cerebral cortex, or ‘cortical thickness’, closely correlates with intellectual ability, however no genes had yet been identified.
An international team of scientists, led by King’s, analysed DNA samples and MRI scans from 1,583 healthy 14 year old teenagers, part of the IMAGEN cohort. The teenagers also underwent a series of tests to determine their verbal and non-verbal intelligence.
Dr Sylvane Desrivières, from the MRC Social, Genetic and Developmental Psychiatry Centre at King’s College London’s Institute of Psychiatry and lead author of the study, said: ‘We wanted to find out how structural differences in the brain relate to differences in intellectual ability. The genetic variation we identified is linked to synaptic plasticity – how neurons communicate. This may help us understand what happens at a neuronal level in certain forms of intellectual impairments, where the ability of the neurons to communicate effectively is somehow compromised.’
She adds: ‘It’s important to point out that intelligence is influenced by many genetic and environmental factors. The gene we identified only explains a tiny proportion of the differences in intellectual ability, so it’s by no means a ‘gene for intelligence’.’
The researchers looked at over 54,000 genetic variants possibly involved in brain development. They found that, on average, teenagers carrying a particular gene variant had a thinner cortex in the left cerebral hemisphere, particularly in the frontal and temporal lobes, and performed less well on tests for intellectual ability. The genetic variation affects the expression of the NPTN gene, which encodes a protein acting at neuronal synapses and therefore affects how brain cells communicate.
To confirm their findings, the researchers studied the NPTN gene in mouse and human brain cells. The researchers found that the NPTN gene had a different activity in the left and right hemispheres of the brain, which may cause the left hemisphere to be more sensitive to the effects of NPTN mutations. Their findings suggest that some differences in intellectual abilities can result from the decreased function of the NPTN gene in particular regions of the left brain hemisphere.
The genetic variation identified in this study only accounts for an estimated 0.5% of the total variation in intelligence. However, the findings may have important implications for the understanding of biological mechanisms underlying several psychiatric disorders, such as schizophrenia, autism, where impaired cognitive ability is a key feature of the disorder.
Paper reference: Desrivières, S. et al. ‘Single nucleotide polymorphism in the neuroplastin locus associates with cortical thickness and intellectual ability in adolescents’ published in Molecular Psychiatry King’s College London
Researchers have made an important advance in understanding genetic changes associated with terminal prostate cancer.
, /in E-News /by 3wmediaFindings show how a genetic mutation in untreated patients is linked to aggressive cancer later in life. It was previously thought that the mutation only occurred in response to therapy.
The research highlights why relapses could occur in some men following hormone therapy. And it could help identify those patients that will develop fatal prostate cancer much earlier for life-extending therapy.
Prostate cancer is the most common cancer in men in the UK, with more than 40,000 new cases diagnosed every year. Treatment options for patients diagnosed with early stage prostate cancer vary from ‘watchful waiting’ to hormone-withdrawal therapy, radiotherapy or surgery.
Additional tests for indicators of aggressive cancer are necessary to help categorise patients so that those with a low-risk of the disease spreading can avoid unnecessary treatment, and those diagnosed with a high-risk can be targeted for more aggressive first line therapy.
Hormone-withdrawal therapy often results in a dramatic remission, however the disease invariably relapses with a resistant form of the cancer. A third of these are due to an increase in copy number of a particular gene called the ‘androgen receptor’. The gene is on the X-Chromosome and so there is normally only one copy of this gene present in men. Prostate cancer thrives on male hormones, and one way that they develop to grow better is to increase the number of copies of the androgen receptor gene. This also enables the cancer to resist therapy.
Lead researchers Dr Jeremy Clark and Prof Colin Cooper from UEA’s school of Biological Sciences carried out the research at the Institute of Cancer Research, London, and at UEA.
Dr Clark said: ‘By the age of 60, the majority of men will have signs of prostate cancer. However, only a small proportion of men will die of the disease. The question is – which of these cancers are dangerous and which are not? Deciding which cancers are going to progress and kill the patient is key to effective patient treatment.’
‘Prostate cancer thrives on male hormones, and cutting the supply of hormones to the cancer is a main avenue of therapy. Prostate cancer only kills the patient when it becomes immune to these therapies. A third of these killer cancers are immune to therapy because they have boosted the number of male hormone receptor (AR) genes in their DNA. This gene boosting, also known as amplification, has been thought to be a response of the tumour to the hormone reduction therapy itself.
‘Our research has shown that an early form of this hormone-gene boosting is present in a number of prostate cancers that have never been treated with hormone reduction therapy. We think that it is these cancers that will grow and kill the patient.
‘This discovery can be used to identify these killer cancers in patients much earlier than is currently possible. Patients could then be selected for more aggressive therapy before the cancer has developed full immunity.’
The research team looked at biomarkers from almost 600 patients prior to hormone-withdrawal therapy. But the method of identification used was labour intensive and time consuming. Developing ways of identifying patients for early therapeutic intervention will be key to implementing this discovery in the clinic. The research team are currently looking at more rapid ways of identifying patients that will develop aggressive cancer. University of East Anglia
Discovery: pre-leukemic stem cell at root of AML, relapse
, /in E-News /by 3wmediaCancer researchers led by stem cell scientist Dr. John Dick have discovered a pre-leukemic stem cell that may be the first step in initiating disease and also the culprit that evades therapy and triggers relapse in patients with acute myeloid leukaemia (AML).
The research is a significant leap in understanding the steps that a normal cell has to go through as it turns into AML, says Dr. Dick, and sets the stage to advance personalised cancer medicine by potentially identifying individuals who might benefit from targeting the pre-leukemic stem cell. AML is an aggressive blood cancer that the new research shows starts in stem cells in the bone marrow. Dr. Dick, a Senior Scientist at Princess Margaret Cancer Centre, University Health Network (UHN), and Professor in the Department of Molecular Genetics, University of Toronto, pioneered the cancer stem cell field by first identifying leukaemia stem cells (1994) and colon cancer stem cells (2007).
‘Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage when it may be more amenable to treatment,’ says Dr. Dick, who holds a Canada Research Chair in Stem Cell Biology and is also Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research (OICR).
‘Now we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse,’ he says.
The findings show that in about 25% of AML patients, a mutation in the gene DNMT3a causes pre-leukemic stem cells to develop that function like normal blood stem cells but grow abnormally. These cells survive chemotherapy and can be found in the bone marrow at remission, forming a reservoir of cells that may eventually acquire additional mutations, leading to relapse.
The discovery of pre-leukemic stem cells came out of a large Leukemia Disease Team that Dr. Dick assembled and included oncologists who collected samples for the Princess Margaret Cancer Centre Biobank and genome scientists at the OICR who developed sophisticated targeted sequencing methodology. With this team, it was possible to carry out genomic analysis of more than 100 leukaemia genes on many patient samples. The findings also capitalised on data from more than six years of experiments in Dr. Dick’s lab involving growing human AML in special mice that do not reject human cells.
‘By peering into the black box of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding. People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells. Our study suggests that in some cases the chemotherapy does, in fact, eradicate AML; what it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and ultimately disease relapse,’ says Dr. Dick, who anticipates the findings will spawn accelerated drug development to specifically target DNMT3a.
These findings should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations and even in non-blood cancers. Princess Margaret Cancer Centre, University Health Network