Scientists have known for decades that the Hox family of transcription factors are key regulators in the formation of blood cells and the development of leukemia. Exactly how this large family of genes, which are distributed in four separate chromosomal clusters named A through D, is regulated has been less clear. Now, new research from the Stowers Institute for Medical Research reveals that a DNA regulatory element within the Hoxb cluster globally mediates signals to the majority of Hoxb genes to control their expression in blood-forming stem cells.
“It’s like we found a general control that simultaneously turns the lights on and off in many rooms, rather than having a single switch that controls each individual room,” says Stowers Investigator Linheng Li, PhD, who co-led the study along with Stowers Scientific Director and Investigator Robb Krumlauf, PhD. These findings also help explain why a particular form of leukemia resists treatment and points to potential new therapeutic avenues.
In mammals, the blood system contains a number of mature cell types — white blood cells, red blood cells, platelets — that arise from blood-forming, or hematopoietic, stem cells (HSCs). HSCs renew themselves and differentiate into other cells to replenish the body’s blood supply in a process called hematopoiesis. Hox genes, which are well known for their roles in establishing the body plan of developing organisms, are also important for HSCs to maintain their critical balancing act in the adult blood system, and have been implicated in the development of leukemia.
In an article Li, Krumlauf, and co-authors including first author Pengxu Qian, PhD, second author Bony De Kumar, PhD, and other collaborators provide new details as to how Hox genes are regulated in HSCs. They report that a single cis-regulatory element, DERARE, works over a long range to control the majority of Hoxb genes in HSCs in a coordinated manner. The researchers found that the loss of the DERARE decreased Hoxb expression and altered the types of blood cells arising from HSCs, whereas “turning on” DERARE allowed Hoxb cluster gene expression in progenitor cells and increased the progression of leukemia.
Genes can be regulated by non-coding DNA sequences termed cis-regulatory sequences. These sequences get input from multiple types of molecules, such as transcription factors, histone modifiers, or various morphogens. The DERARE, or distal element RARE (retinoic acid response element), is a cis-regulatory element that responds to signals from the vitamin A derivative retinoic acid and determines the fate of HSCs.
Using human leukemia cell lines and mouse models, the Stowers researchers and collaborators have identified a mechanism for how the retinoid-sensitive DERARE maintains normal hematopoiesis and prevents acute myeloid leukemia (AML) by regulating Hoxb cluster genes in a methylation-dependent manner.
Methylation is the process of adding methyl groups to the DNA molecule, which can change the activity of the DNA segment. The researchers demonstrated that DNA methyltransferases mediate DNA methylation on DERARE, leading to reduced Hoxb cluster expression. AML patients with mutations in the DNA methyltransferase DNMT3A exhibit reduced DERARE methylation, elevated Hoxb expression, and adverse outcomes.
“In two human AML cell lines carrying a DNMT3A mutation, we used an adaptation of genome editing technology called dCas9-DNMT3A to specifically increase the DNA methylation on DERARE. This targeted methylation technique was able to reduce Hoxb cluster expression and alleviate the progression of leukemia,” says Qian. “It is known that Hoxb cluster genes show a dramatic increase in expression in patients with DNMT3A-mutated AML. Our work provides mechanistic insights into the use of DNA methylation on the DERARE as a potential screening tool for therapeutic drugs that target DNMT3A-mutated AML, thus leading to the development of new drugs for treating AML, in which DNA methylation is abnormal.”

Stowers Institutehttps://tinyurl.com/yarf3xfd

Hong Kong Baptist University (HKBU) Chemistry scholars have invented a new class of multifunctional cyanine compounds that can be used for detection, imaging and thus treatment of Alzheimer’s disease. The discovery has been granted four US patents and a patent by the Chinese government.
The research team was jointly led by Professor Ricky Wong Man-shing and Associate Professor Dr Li Hung-wing with members from the Department of Chemistry of HKBU. By making use of the proprietary compounds, the HKBU team, on one hand, has proved that the cyanine compounds applied onto a “nano”-detection platform can quantify trace amounts of Alzheimer’s disease related protein biomarkers present in human fluids such as cerebrospinal fluid, serum, saliva, and urine. It is a rapid, low-cost and ultrasensitive detection assay. On the other hand, the compounds also serve as an imaging agent for in vivo detection and monitoring of disease progression and understanding the disease pathogenesis as well as a drug candidate for treatment of the disease.
Alzheimer’s disease is the most common neurodegenerative disorder, it is incurable and the underlying cause is still not well understood. Alzheimer’s disease is characterized by the formation of amyloid plaque in human brains. Clinical evaluation, cognitive tests and neuroimaging (monitoring the brain’s structural changes) are commonly used to diagnose Alzheimer’s disease, but are only effective after symptoms appear. Moreover, neuroimaging, such as magnetic resonance imaging (MRI), requires injecting contrast agents into a person that may bring health risks.
The proteins of interest, namely beta amyloid peptide, tau, and p-tau, in human’s cerebrospinal fluid are linked to Alzheimer’s disease. The versatile detection assay using the compounds developed by the team requires only a minute amount of the sample fluids (a few microliters) to reliably quantify the target proteins. The detection assay developed by the team is fast, cheaper and more sensitive than traditional commercially available biological methods.
Detection is based on the specific immuno-interactions between the target antigen and detection antibody that is immobilised on the surface of magnetic nanoparticles. The sandwiched immuno-assembly is then labelled with a newly developed turn-on cyanine compound that enhances the fluorescence signal, which is quantified by an imaging system.
Dr Li said, “This newly developed assay will be particularly useful as a low-cost yet accurate diagnostic and prognostic tool for Alzheimer’s disease. It can also serve as a novel alternative non-invasive tool for population-wide screening for the disease. This scientific detection assay has a high potential to serve as a practical diagnosis tool.”
Dr Li said that the new approach is universal and general enough to be readily modified and elaborated further, such as replacing the antibodies with other disease-associated antibodies, nucleic acids, for a broad range of biomedical research and disease diagnostics.   
Hong Kong Baptist Universityhkbuenews.hkbu.edu.hk/?t=press_release_details/2196

Atrial fibrillation (AF) is a heart condition that causes an irregular, and often rapid, heart rate. It increases the risk of developing strokes, heart failure, and even dementia. Although it can be associated with aging, high blood pressure, diabetes, heart valve problems, etc, about one-third of patients with AF have no symptoms until they suffer a stroke. Therefore, a means of identifying or predicting AF with the aim of starting preventative therapy is highly desirable.
AF is associated with several factors that maintain its progression, including inflammation, electrical disturbances, and structural changes in the heart’s upper chambers (the atria). Moreover, several different short sequences of RNA known as microRNAs (miRNAs) have been linked with AF pathology. miRNAs control gene expression after the transcription stage, and have been suggested as possible markers for some cardiovascular diseases because of their stability in the bloodstream. However, it remains unknown whether the miRNAs shown to be related to AF are suitable as predictive biomarkers of disease.
A team of researchers from Tokyo Medical and Dental University (TMDU) addressed this issue by comparing miRNA expression in AF patients and healthy controls, and between control mice and those with a similar abnormal heart rhythm to AF. They showed that four miRNAs not previously associated with AF were significantly upregulated in the serum of AF patients and diseased mice, indicating their potential use as AF biomarkers. The study results were recently published in Circulation Journal.
Initially, human serum and mouse atrial tissue were screened for 733 and 672 miRNAs, respectively. These were eventually narrowed down to four by excluding non-detectable and non-specific miRNAs, and focusing on the quantification of their expression.
“One of the miRNAs, miR-214-3p, is implicated in inflammation, so we wondered whether this might be the underlying mechanism of miRNA-induced AF pathology,” first author Yu Natsume says. “We compared miRNA expression with levels of a serum inflammatory factor but found no correlation suggestive of an association.”
Statistical analysis of diagnostic ability showed that miR-214-3p and miR-342-5p had the highest accuracy as individual biomarkers at predicting AF, but that a combined analysis of all four miRNAs slightly improved this accuracy.
“The same two miRNAs showed increased expression in a subset of patients with intermittent AF and another subset with chronic AF,” corresponding author Tetsuo Sasano says. “The increases were in comparison both with healthy controls of the same age and young healthy controls, suggesting these miRNAs may predict AF regardless of the age of the individual.”
Tokyo Medical and Dental University (TMDU)www.tmd.ac.jp/english/press-release/20180313/index.html

Orion Corporation (“Orion”) had announced last January that it was evaluating strategic alternatives of the Group’s Orion Diagnostica business division and had decided to investigate the possible sale of Orion Diagnostica as one alternative. Orion has now signed an agreement on the sale of all shares in Orion Diagnostica Oy (i.e. the Orion Diagnostica business division) to an investment fund managed by Axcel Management A/S, a leading Nordic private equity investment company (“Axcel”). The closing of the transaction is expected to take place during the second quarter of 2018. The closing is not conditional upon the parties obtaining approvals from competition law or other authorities or fulfilment of other preconditions.
The fixed purchase price is approximately EUR 163 million. In addition, Orion has a possibility to receive a variable component of EUR 60 million maximum. The payment of this variable component is based on return on investment for Axcel at the time of their exit. Orion estimates a capital gain of about EUR 128 million in other operating income for 2018. Due to the uncertainty relating to the variable component, the estimated capital gain does not include any part of the variable component.
“Orion Diagnostica has operated as an independent business and it has no material business synergies with Orion’s other operations. The sale of the division will allow us to further focus on growth and achieving our financial goals. Orion is currently working on numerous projects that target growth in our core area of the pharmaceuticals business. For example, we are actively evaluating late stage in-licensing opportunities. We also continue to invest in our own research and development activities, with new clinical trials, for example. The capital gain from the transaction will strengthen our equity position and maintain our ability to achieve our dividend distribution objective”, says Timo Lappalainen, President and CEO of Orion.
“Together with Orion Diagnostica’s management and employees, we intend to further develop the company into an even stronger operator in the global diagnostics market. On the back of an attractive customer proposition and a strong market position, we see great opportunity to grow Orion Diagnostica further both geographically and by expanding its product offering”, says Thomas Blomqvist, Partner at Axcel.
www.oriondiagnostica.com

Patients with gallbladder cancer often show few or no symptoms for long periods of time. As a result, the tumours are only detected at a late stage of the disease when treatment is often no longer possible. Working in collaboration with pathologists at the University of Magdeburg, Sonja M. Kessler, a research pharmacist in the group led by Professor Alexandra K. Kiemer at Saarland University, has identified a new pathway that may allow improved prognosis and treatment of the disease. Kessler has discovered a protein that is linked with tumour growth and that functions as a prognostic marker, thus providing an indication of how the cancer may progress.
The three proteins usually targeted by pharmacist Sonja M. Kessler in her research work are known to play an important role in embryos in the womb. These proteins help to ensure the rapid growth and development of the unborn child. After birth, however, these proteins typically play no further role. ‘All of these proteins are switched off after birth and they are no longer copied from the child’s genetic blueprint,’ explains licenced pharmacist Dr. Sonja M. Kessler, who is carrying out research at Saarland University in the group run by Professor Alexandra K. Kiemer for her Habilitation – the advanced research degree that entitles the holder to teach at professorial level within the German higher education system. However, it turns out that this family of proteins with the unremarkable names IMP1 to 3 can be switched on again. And if that happens, they can cause a lot of harm. Of the three proteins, IMP2 is particularly hostile: ‘Because IMP2 promotes cell division and proliferation, it also drives the growth of tumours,’ explains Kessler.
Research pharmacist Kessler has now succeeded in linking the protein group to gallbladder cancer. ‘We were able to identify the proteins in a large number of tissue samples from gallbladder patients. We were also able to show that the tumour grows faster when the cells contain larger amounts of the IMP2 protein. And in those cases patient prognosis is poorer,’ says Kessler.
This result from a basic research programme may in future help to improve gallbladder treatment. ‘Up until now there have been very few prognostic markers for this tumour,’ says Sonja Kessler. Prognostic markers are substances in blood or tissue samples that indicate that a malignant cancer is likely to have a poor outcome for the patient. Currently available treatment options can therefore be tailored more closely to the patient’s needs, which may help to improve clinical outcomes. IMP2 represents an important and potentially useful prognostic marker for gallbladder cancer. The results of Kessler’s research may also provide the basis for new effective drug treatments. Once the participating protein has been identified, research can be undertaken to influence, slow or even completely prevent the harmful processes that are set in motion by the protein.
University of Saarlandes
www.uni-saarland.de/nc/en/news/article/nr/18177.html