Acute and aggressive leukemia such as multilineage leukemia (MLL) develops and progresses rapidly in patients, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant, but such treatments can be risky or only partially effective. At present, only 70% of people with acute myeloid leukemia respond initially to standard chemotherapy, with a 5-year survival rate between 15 and 70%, depending on the subtype of acute myeloid leukemia; as such, researchers are searching for improved and more targeted treatment strategies
Now, a study published in Nature Genetics points to a molecular pathway involving the gene SETD2, which can mutate in blood cells during a critical step as DNA is being transcribed and replicated, identifying a novel molecular target for treating recurring and deadly malignancies.
The study utilized a unique and rare opportunity to compare the whole genomes of monozygotic twin sisters, one healthy and one with MLL. “We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events,” explained Gang Huang, co-corresponding author and a researcher in the divisions of Pathology and Experimental Hematology and Cancer Biology at Cincinnati Children’s Hospital Medical Center (OH, USA). He continued, “This provided a strong basis for comparison and analysis.”
Using whole-genome sequencing the team discovered that the activation of MLL-NRIP3 fusion leukemia started the molecular cascade that led to biallelic mutation in the gene SETD2, a tumor-suppressor gene that codes an enzyme known to regulate a specific histone-modification protein H3K36me3, “We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells,” commented Huang.
The researchers then analyzed blood samples from patients who had different forms of acute leukemia and found that loss-of-function point mutations in SETD2 were recurrent in 6.2% of 241 patients with acute leukemia, and were associated with multiple major chromosomal aberrations. They observed a global loss of H3K36me3 in leukemic blasts with mutations in SETD2. In addition, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells in the presence of a genetic lesion.
“Our study provides compelling evidence for SETD2 as a new tumor suppressor,” concluded the authors, “Disruption of the SETD2–H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development.” The team is now following up their current study by identifying additional pathways activated by mutations of SETD2, as well as looking at possible new molecular targets and therapeutic strategies for block disruptions in the MLL fusions–SETD2–H3K36me3 pathway.
– Written by Ruth Williamson
Sources: Xiaofan Z, Fuhong H, Huimin Z et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nature Genetics 46, 287–293 (2014); Study involving twin sisters provides clues for battling aggressive cancers: www.cincinnatichildrens.org/news/release/2014/leukemia-research-02-09-2014
By using transgenic zebrafish as whole animal models, in combination with cultured cells and data from human tumors, researchers from the Icahn School of Medicine at Mount Sinai (NY, USA) have demonstrated that high expression of the gene UHRF1 can cause liver cancer at an unprecedented rate and incidence, causing tumors to form in 75% of fish within 20 days.
“This is the first time that UHRF1 has been shown to be sufficient on its own to cause any kind of cancer when it is highly expressed,” commented the study’s senior investigator, Kirsten C Sadler (Icahn School of Medicine at Mount Sinai, NY, USA)
UHRF1 is overexpressed in around 40–50% of hepatocellular cancers in humans and is associated with poorer prognosis in terms of high recurrence rate and low overall survival.
UHRF1 has generated a great deal of interest as it is a central regulator of the epigenome. The cancer cell epigenome is dramatically different from normal cells and it is hoped that research in the field of cancer epigenetics could allow some of these changes to be reversed, subsequently reversing the aggressive nature of cancer cells. “We have little to offer people in the setting of advanced disease – and this points to an entirely new direction,” added Sadler. “It raises the hope that epigenetic drugs could be applied to liver cancer in the future.”
The research team, which also included researchers from Harvard Medical School’s Brigham and Women’s Hospital (MA, USA), Institut d’Investigacions Biomèdiques August Pi i Sunyer (Barcelona, Spain) and Institucio Catalana de Recerca (Barcelona, Spain) also analyzed patient-derived liver tumors and observed high levels of expression of UHRF1.
The changes in gene expression caused by high UHRF1 levels in zebrafish were reflected in the human tumors expressing high UHRF1 levels. This points to similar mechanisms underlying UHRF1-driven liver tumor formation in both species. One of these is the ability of the cancer-prone cells to bypass the tumor suppressive mechanisms that are activated in most cells when they receive a cancer-causing stimulus. Cellular senescence is one such mechanism, and this study found that in tumors associated with UHRF1 levels in both fish and humans, only those cells that could escape senescence were the ones that could go on to form tumors. This potentially lays the groundwork to use this model to test new therapies that would target UHRF1 to reactivate the senescence program and halt cancer formation.
“Down the road, we hope to develop drugs to target UHRF1 and thereby reset the cancer epigenome to activate anti-tumor mechanisms and halt liver cancer.” added Dr Sadler.
Results from the study are published online in the journal Cancer Cell.
– Written by Emma Sinclair
Source: Mudbhary R, Hoshida Y, Chernyavskaya Y et al. UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer Cell 25(2), 196–209 (2014).
Research published in Nature Structural and Molecular Biology from the Karolinska Institutet (Solna, Sweden) has revealed how an epigenetic change is critical for the correct segregation of chromosomes. For proper cell division to take place, functional centromeres are required; errors in their structure can lead to an abnormal number of chromosomes, which can be associated with cancer development. The current study has demonstrated how the attachment of a small protein to a particular histone influences structural changes in the centromere prior to cell division.
In normal cell division, chromosomes are divided equally into two daughter lines; however, tumor cells are often found to have an incorrect number of chromosomes which leads to abnormal gene expression. It is already known that epigenetic processes play an important role in the establishment of centromeres through the incorporation of the histone H3 variant CENP-A. This latest research has demonstrated the direct involvement of H2B monoubiquitnation in centromeric chromatin maintenance mediated by RNF20 in humans or Brl1 in Schizosaccharomyces pombe. It was found that Monoubiquibnated H2B (H2Bub1) promotes noncoding transcription, centromere integrity and accurate chromosomal segregation. H2Bub1 appears to affect RNA polymerase II-mediated transcription of the centomere’s central domain, as well as H3 instability.
In addition, it was observed that H2Bub1-deficient cells exhibited characteristics of heterochromatin, such as the silencing of histone modifications, reduced nucleosome turnover and reduced levels of transcription. This meant that the functionality of the centromere was diminished, leading to unequal chromosome segregation.
Peter Svensson, one of the study authors, explained the next step of his group’s research: “Our study confirms this role for H2Bub1, but we are extending it to include another mechanism that directly leads to the incorrect number of chromosomes in cells.” Through research such as this, it is hoped that investigating epigenetic mechanisms will help scientists understand pathways that could be targeted to protect against cancer.
– Written by Jonathan Wilkinson
Sources: Karolinska Institutet News: http://ki.se/en/news/epigenetic-regulation-required-to-ensure-correct-number-of-chromosomes; Sadeghi L, Siggens L, Svensson JP, Ekwall K. Centromeric histone H2B monoubiquitination promotes noncoding transcription and chromatin integrity. Nat. Struct. Mol. Biol. 21(3), 236–243 (2014).
In a recent study published in Nature Communications, researchers from King’s College London (UK) have discovered that pain sensitivity may be modified by lifestyle and environmental factors that lead to epigenetic changes.
The underlying molecular mechanisms of pain sensitivity are not fully understood. Until this study, it was previously assumed that this was a relatively inflexible phenomenon. Identical twins are an ideal subject group in which to test environmental and epigenetic effects as they share the same genetic makeup, meaning that any differences must be a result of these factors.
The team tested 25 pairs of identical twins, as well as 50 unrelated individuals. Using a heat probe on the arm, participants were asked to indicate when a sensation became too painful, thereby providing a measure of their pain thresholds. Using DNA sequencing, whole-blood DNA methylation was characterized at 5.2 million loci in order to identify differentially methylated regions associated with high or low pain sensitivity.
The researchers identified chemical modifications within nine genes involved in pain sensitivity that were discordant between twins. The most significant changes were associated with TRPA1, a known pain sensitivity gene that is already a therapeutic target in analgesic development. Establishing the mechanisms by which TRPA1 may be ‘switched on and off’ epigenetically could have major implications for tackling pain relief.
Tim Spector, Professor of Genetic Epidemiology at King’s College London has stated that “Epigenetic switching is like a dimmer switch for gene expression. This landmark study shows how identical twins, when combined with the latest technology to look at millions of epigenetic signals, can be used to find the small chemical switches in our genes that make us all unique – and in this case respond to pain differently.”
The lead author of the study, Jordana Bell, concludes that “The potential to epigenetically regulate the behaviour of TRPA1 and other genes involved in pain sensitivity is very exciting and could lead to a more effective pain relief treatment for patients suffering with chronic pain.”
–Written by Caroline Telfer
Source: Pain sensitivity may be influenced by lifestyle, environment, twin study suggests: www.sciencedaily.com/releases/2014/02/140204112123.htm