Acute Myeloid Leukemia (AML) is an aggressive form of blood cancer that frequently develops in children. The diseased cells often carry mutated forms of a specific gene, which is known to function within large protein networks. Researchers at CeMM and LBI-CR identified a protein of this network crucial for the survival of the cancer cells – a novel potential approach for targeted therapies. The study was published in Nature Communications.
AML is not a single disease. It is a group of leukemias that develop in the bone marrow from progenitors of specialized blood cells, the so-called myeloid cells. Rapidly growing and dividing, these aberrant cells crowd the bone marrow and bloodstream, which can be fatal within weeks or months if the disease is left untreated. Myeloid cells of various types and stages can become cancerous and cause AML, which makes the condition very heterogeneous and difficult to treat. Thus, finding drug targets that affect as many forms of AML as possible is a prime goal for researchers.
The research groups of Florian Grebien from the Ludwig Boltzmann Institute for Cancer Research, Giulio Superti-Furga, Scientific Director of the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and Johannes Zuber, from the Institute of Molecular Pathology, tackled that question in their latest study. They were able to identify common, conserved molecular mechanisms that drive oncogenesis in the context of the large number of different MLL-fusion proteins by characterizing the protein-protein interaction networks of distantly related MLL fusion proteins. Their results were now published in Nature Communications (DOI:10.1038/s41467-018-04329-y)
The scientists identified the methyltransferase SETD2 as a critical effector of MLL-fusion proteins. Using genomic techniques including CRISPR/Cas9 genome editing, the researchers found that SETD2 loss caused induction of DNA-damage and ultimately cell death in the cancer cells. Moreover, SETD2 loss increased the lethal effect of Pinometostat, a drug that is currently in clinical development for treatment of leukemia patients with MLL fusions. These experiments might pave the way for a more effective therapy in the future using a combination of compounds.
Anna Skucha, Jessica Ebner, Johannes Schmöllerl, Mareike Roth, Thomas Eder, Adrián César-Razquin, Alexey Stukalov, Sarah Vittori, Matthias Muhar, Bin Lu, Martin Aichinger, Julian Jude , André C. Müller, Balázs Győrffy, Christopher R. Vakoc, Peter Valent, Keiryn L. Bennett, Johannes Zuber*, Giulio Superti-Furga* and Florian Grebien* (*equal contribution). MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity. Nature Communications, 2018. DOI:10.1038/s41467-018-04329-y
The study was funded by the European Commission, the European Research Council (ERC), the Austrian Science Fund (FWF), the Austrian Research Promotion Agency (FFG), the National Institutes of Health (NIH), the National Research, Development and Innovation Office, Hungary, and Boehringer Ingelheim.
The first line of immune defense against invading pathogens like bacteria are macrophages, immune cells that engulf every foreign object that crosses their way and kill it with acid, in a process called phagocytosis. In their quest to systematically study proteins that transport chemicals across cellular membranes, researchers at CeMM characterized the critical role for transporter SLC4A7 in this process, providing valuable new insights for many pathologic conditions from inflammation to cancer. Their results were published in Cell Host & Microbe.
Among the many different kinds of immune cells that patrol the body, macrophages are the first when it comes to fight against a foreign threat. With their flexible and versatile surface, they engulf every microorganism or particle that could be harmful for the health of the organism, and enclose it in an intracellular membrane vesicle called phagosome. To eliminate the threat and break it down to its constituents, the interior of the phagosome needs to be effectively and progressively acidified. For this crucial part of phagocytosis, the macrophages must undergo multiple metabolic changes, which are not yet entirely understood.
The team of Giulio Superti-Furga, Scientific Director of CeMM, in collaboration with the laboratory of Nicolas Demaurex of the University of Geneva, discovered in their latest study that a membrane protein belonging to the family of “solute carriers” (SLCs) plays an essential role in phagocytosis and phagosome acidification. Their work was published in the journal Cell Host & Microbe (DOI 10.1016/j.chom.2018.04.013).
The researchers developed an essay with special cells in which they impaired the 391 human SLC genes individually using CRISPR/Cas9 gene editing technology. Strikingly, among all SLCs, SLC4A7, a sodium bicarbonate transporter, was the only one who turned out to be essential for macrophages to undergo phagocytosis and acidification. Cells with impaired SLC4A7 were unable to acidify their phagosomes and by consequence decreased their capacity to kill bacteria.
The results of this study do not only provide new fundamental insights into the molecular functioning of one of the most important cells of the immune system. As phagocytosis plays a significant role in various pathologic conditions from inflammation to cancer, these new insights are likely of relevance beyond the context of infectious diseases. The effort to understand the role of the different cellular transporters, supported by a grant of the European Research Council (ERC), has added a small new piece to the large and fascinating puzzle coupling trafficking of chemical matter to metabolism and cellular function.
Vitaly Sedlyarov, Ruth Eichner, Enrico Girardi, Patrick Essletzbichler, Ulrich Goldmann, Paula Nunes-Hasler, Ismet Srndic, Anna Moskovskich, Leonhard X. Heinz, Felix Kartnig, Johannes W. Bigenzahn, Manuele Rebsamen, Pavel Kovarik, Nicolas Demaurex, and Giulio Superti-Furga. The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification. Cell Host & Microbe, 2018. DOI: 10.1016/j.chom.2018.04.013
The study was funded by the European Research Council (ERC), the Austrian Academy of Sciences, the Austrian Science Fund (FWF), the European Commission, and the European Molecular Biology Organization (EMBO).
At the 12th CeMM Landsteiner Lecture, held by Yasmine Belkaid, Director of the NIH Center for Human Immunology and Director of the NIAID Microbiome Program, everything revolved around one of the most important emerging fields of research in life sciences: the microbiome. Yasmine Belkaid explained how microorganisms living in and on our bodies influence every aspect of our immune system, and why research in this field will change the medicine of the future.
We carry around nearly the same number of microbes as we have cells in our body, yet those microscopic symbionts express a hundred times more genes than human cells. This ratio, which Yasmine Belkaid presented at the beginning of her lecture, gave the audience a first impression of the magnitude of the microbiome’s influence.
The communities of bacteria, protists, fungi and viruses that reside throughout the human body affect many aspects of its physiology. However, the immune system is by far the most tightly interwoven part. Refuting the old paradigm of an immunity whose sole purpose is to defend the body against invading pathogens, Yasmine Belkaid showed how it constantly interacts with the commensal microbes and how those single celled organisms control the immune cells with a mind-blowing precision.
Among the many examples of her groundbreaking research, Yasmine highlighted the finding that single types of microbes are able to engage specific kinds of immune cells, like the CD8 lymphocytes which are promoted by S. epidermidis. Without causing inflammation, this specific interaction contributes to the protection of the skin against the infection with a pathogen. Yasmine Belkaid further described how “mysterious” non-classical MHC-I molecules present commensal antigens in the establishment of a homeostatic immunity and how CD8+ T cell inducing bacteria even promote wound healing.
To understand the profound alliance between the microbiota and the immune system in detail, Yasmine Belkaid concluded her talk, will be a major progress for combating a broad range of medical conditions, from infection to inflammation to cancer.
370 scientists of different fields and interested lay people showed with a long-lasting applause and many questions their appreciation of Yasmine Belkaid´s outstanding talk. The baroque festive hall of the Austrian Academy of Sciences was filled to the last place and many more followed the lecture via video stream in an adjacent room. Framed by the music of Bela Koreny and Ethel Merhaut, who delightfully performed two Viennese songs, the evening was rounded off with a cocktail reception and lively discussions.
Our warmest thanks to Yasmine Belkaid for this wonderful 12th CeMM Landsteiner Lecture!
Image Gallery CeMM Landsteiner Lecture 2018
Former CeMM Landsteiner Lectures
A video of Yasmine Belkaids Lecture will be available soon.
DNA mutations driving cancer development are caused by different mechanisms, each of them leaving behind specific patterns, or “scars” in the genome. Using CRISPR-Cas9 technology, researchers at CeMM and the Wellcome Trust Sanger Institute at Cambridge, UK were able to show for the first time in cell culture that specific genetic alterations indeed lead to the predicted pattern of mutational signatures observed in human cancers. The results were published in Nature Communications (DOI: 10.1038/s41467-018-04052-8).
When a cell develops into a tumor, something has gone terribly wrong: the uncontrolled growth, invasion of nearby tissues and finally metastasis are the result of many consecutive DNA mutations. Such an accumulation of demolished genetic material often derives from initial environmental exposures, enzymatic activities or defects in DNA replication or DNA repair mechanisms. Each of those initial mutagenic conditions creates their own pattern of DNA damage called mutational signature. Deciphering them could theoretically allow us to trace back the initial cause of a tumor, profile its properties and help find a therapeutic strategy.
However, reading those mutational signatures in tumor samples is a difficult task, as the large amount of mutations that a patient acquires during its lifetime create a noisy and uncontrolled system – even the best clinical data will, at most, provide only associations. Therefore, the group of Joanna Loizou, Principal Investigator at CeMM in collaboration with researchers from the Wellcome Trust Sanger Institute, developed an experimental setup to validate the concept of mutational signatures in cell culture.
The findings of this study not only confirm an analytical principle that describes mutational processes and cancer development, mutational signatures are a direct mechanistic read-out of specific dysfunctions of a cell. Thus, even if the underlying gene defect is unknown, mutational signatures could be used as biomarkers for the molecular characterization of tumors – a new diagnostic tool to improve the precise and personalized treatment of cancer.
Xueqing Zou*, Michel Owusu*, Rebecca Harris, Stephen P. Jackson, Joanna I. Loizou#, Serena Nik-Zainal# (*These authors contributed equally to this work # Corresponding authors). Validating the concept of mutational signatures with isogenic cell models. Nature Communications 9, 2018. DOI: 10.1038/s41467-018-04052-8.
The study was funded by the Austrian Academy of Sciences, the European Commission (Marie-Curie Career Integration Grant), the Austrian Science Fund FWF and the Wellcome Trust.
The 8th CeMM S.M.A.R.T. Lecture held by architect and urban design consultant Jan Gehl was exceptionally entertaining and inspiring. It illustrated with many captivating examples the problems cities developed in the 20th century by pursuing an object- instead of a people-centered city planning and how simple measures can make cities livable.
“We knew more about the natural habitat of the mountain gorilla or the Siberian tiger than about the Homo sapiens’ living space” – with this provoking citations, Jan Gehl displayed the vast lack of knowledge that lead to some of the 20th centuries biggest challenges for modern cities. By building in an objects- and road-focused manner, a typical approach for the era of modernism and “motorism” in architecture, urban planners forgot about creating livable spaces for people. Instead, huge buildings and vast roads were built for cars, a now outdated and inefficient transportation technology, as Jan Gehl pointed out.
In consequence, many modern cities today are not only ugly and unpleasant to live in, but also unhealthy. The emphasis on mobility, meaning the use of automobiles, lead to the so-called “sitting syndrome”, a lack of physical exercise that has become a mayor health threat. To counteract those developments, Jan Gehl pioneered an observation-based city planning by systematically documenting urban spaces, making gradual incremental improvements, then documenting them again.
His results are impressive: measures like banning cars from city centers, creating extensive and coherent biking lanes and designing nice and “sticky” places that people like to use, turned Copenhagen, where Jan Gehl was involved in the urban planning for over 40 years, from a car-dominated city into one of the most livable places in the world. Many other cities, including New York and Moscow, sought advice from Jan Gehl and improved their urban space with his help.
A crowded seminar hall at CeMM with an audience of somewhat 150 people with all kinds of backgrounds followed this S.M.A.R.T. Lecture eagerly and engaged in lively discussions afterwards. Artist, architects, city planners and scientists met Jan Gehl in the brain lounge for an intense discussion round. We are proud, honored, and most thankful that Jan Gehl followed our invitation, and supports our efforts to foster the interdisciplinary discourse, widen our horizons and establish a dialogue with the broader public. The quality of our research is strongly influenced by the quality of our environment and creativity flourishes in inclusive, integrative and livable cities.
His take home message will remain firmly etched into our memories: The world is not about getting from A to B, the world is about having nice places to be!
Lymphocytic choriomeningitis virus (LCMV) served as an indispensable model system for chronic viral infections over the last 80 years; two Nobel prizes were awarded for its exploration. However, the molecular interactions during the life cycle of the virus were hitherto poorly understood. In a new study, published in PLOS Pathogens, CeMM scientists revealed the comprehensive set of cellular proteins that physically interact with the LCMV polymerase – a key enzyme for the development of a chronic infection.
Chronic viral infections like HIV or hepatitis are among the biggest threats to human health worldwide. While an acute viral infection usually results in a full recovery and effective immune memory, chronic viruses evade the immune system and remain permanently in their host´s body. Treating such a disease is a difficult task, as the molecular events during the development of a chronic infection remained largely elusive.
With their latest study published in PLOS Pathogens (DOI 10.1371/journal.ppat.1006758) the team of Andreas Bergthaler, Principal Investigator at CeMM, in cooperation with the University of Basel and the MRC Laboratory of Molecular Biology Cambridge made an important contribution to the understanding of chronic viral infections: the scientists established the first comprehensive overview of cellular proteins interacting with the LCMV polymerase, a crucial enzyme for the replication of the virus and for chronic infection. By mapping them in the human proteome, they revealed various viral strategies and potential targets for future antiviral therapeutics.
In order to perform the study, the researchers – with CeMM PhD student Kseniya Khamina as first author – developed a novel approach to tag viral proteins. Therewith, the interactions of the LCMV polymerase with the proteins of the host cells were determined. Combined with publicly available data from other RNA viruses’ polymerase interactomes, the generated dataset allowed a mapping of the cellular pathways targeted by different viral polymerases. Some of the proteins found to interact with the LCMV polymerase turned out to be essential for the viral life cycle.
Kseniya Khamina, Alexander Lercher, Michael Caldera, Christopher Schliehe, Bojan Vilagos, Mehmet Sahin, Lindsay Kosack, Anannya Bhattacharya, Peter Májek, Alexey Stukalov, Roberto Sacco, Leo C. James, Daniel D. Pinschewer, Keiryn L. Bennett, Jörg Menche, and Andreas Bergthaler. Characterization of host proteins interacting with the lymphocytic choriomeningitis virus L protein. PLOS Pathogens, December 20, 2017. DOI: 10.1371/journal.ppat.1006758
The study was funded by the City of Vienna and the Austrian Academy of Sciences.
We congratulate Barbara Mair to the highest possible honor for achievements in university studies - the promotion sub auspiciis praesidentis rei publicae, Alexander Van der Bellen. The ceremony was held in the Van Swieten Hall of the Medical University of Vienna.
Straight A´s from high school until the end of the doctorate, graduation within a given time scale, accompanied by exemplary moral character – in order to qualify for the honor of a promotion sub auspiciis praesidentis, an individual has to meet the highest possible demands. Since 1952, slightly more than 1000 students graduated sub auspiciis. Barbara Mair now belongs to this academic elite, as well as Eliana Montanari, former PhD Student at the Medical University of Vienna, who was also honored today.
Federal President Alexander Van der Bellen presented the graduates with the gold ring, engraved with the words "sub auspiciis praesidentis" and the emblem of Austria, as a sign of recognition from the Republic of Austria. In his speech, he expressed his admiration for the exceptional endurance and curiosity, which are necessary – besides exceptional talent and intelligence – for such outstanding achievements. Rector of the Medical University Markus Müller, who himself graduated sub auspiciis, welcomed the audience with a brief historical overview of the sub auspiciis tradition.
CeMM Scientific Director Giulio Superti-Furga emphasized in his laudation Barbara Mair’s stellar impression she made from the very first moment: she applied for a PhD position at CeMM with an already impressive CV, especially with respect to her achievements and top grades during high school and undergraduate studies, with distinction in Molecular Biology (Mag.rer.nat.) and in Spanish literature and linguistics (BA). In 2011, she started her Ph.D. studies at CeMM, in Sebastian Nijman’s group as the top ranked student from over 400 applicants and continued to impress with her sharp and critical intellect paired with ambition, diligence, persistence, and hard work. Barbara stayed at CeMM until Sebastian Nijman’s lab moved to Oxford (December 2014), still registered with Medical University of Vienna continued her studies. Barbara completed her PhD with an excellent thesis and an impressive public defense of her work. Her ambition also expands into her spare time, where she – among others - competes in Austria’s and Great Britain’s first and second handball leagues and won the All British University Handball Championships in 2016.
We are more than proud, and want to express our warmest congratulations to Barbara Mair her truly exceptional achievements!
Congratulations to Giulio Superti-Furga, CeMM´s Scientific Director, Miriam Unterlass, Technical University of Vienna, and Stefan Kubicek, CeMM for winning one of the WWTF 2017 Life Science Grants on Chemical Biology. In the project called “3C - Cellular color chart” the research team aims to generate new fluorescent molecules that probe intracellular processes with a full molecular understanding of their biological specificity.
This proposal is made possible by the existing expertise and infrastructure of the project partners. The laboratories of Giulio Superti-Furga and Stefan Kubicek, especially the Platform Austria for Chemical Biology at CeMM, have extensive experience in the handling of compound libraries and phenotypic screening using automated high-content microscopy. And Miriam Unterlass is an expert in chemical synthesis and provides knowledge and infrastructure for the efficient generation of analogs of the fluorescent molecules identified from chemical screening. CeMM is looking forward in entering this research collaboration with a member from the Technical University of Vienna.
Giulio Superti-Furga, CeMM
Miriam Unterlass, TU Vienna
Stefan Kubicek, CeMM
The next PhD Program at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna will start in October 2018. We offer 15 fully funded PhD positions and are looking for exceptionally motivated PhD candidates with a keen interest in genomics, medicine and interdisciplinary teamwork.
+++ Apply now! The application deadline is 2nd February 2018 +++
The 2018 CeMM PhD Program will focus on the thematic areas of Infection, Immunity, Metabolism, Cancer and Network Medicine. These areas are built on the pillars of epigenetics and genome integrity, bioinformatics and systems biology, chemical biology, high-throughput genetics, genomics and proteomics, and molecular and cell biology.
CeMM is an international research institute of the Austrian Academy of Sciences. The mission of CeMM is to achieve maximum scientific innovation in molecular medicine to improve healthcare. At CeMM, an international and creative team of scientists and medical doctors pursues free-minded, basic life science research in a large and vibrant hospital environment of outstanding medical tradition and practice. CeMM operates in a unique mode of super-cooperation, connecting biology with medicine, experiments with computation, discovery with translation, and science with society and the arts. The goal of CeMM is to pioneer the science that nurtures the precise, personalized, predictive and preventive medicine of the future.
CeMM is located at the center of one of the largest medical campuses in Europe, within walking distance to Vienna’s historical city center. Vienna is repeatedly ranked as the world’s best city to live in and is a United Nations city with a large international, English-speaking community. The official language at CeMM is English, and more than 40 different nationalities are currently represented at the institute.
The successful candidates will be awarded a generous scholarship, which covers all research costs, university fees, work-related travel expenses, salary and health insurance for 4 years. The PhD degree will be awarded by the Medical University of Vienna.
To be eligible to enroll in the CeMM PhD Program, all candidates are required to have a final degree (minimum requirement is a four-year Bachelor’s degree) in medicine, biology, chemistry, bioinformatics, computer science, engineering, physics, mathematics or a similar subject. The working language at CeMM is English, i.e. excellent written and oral communication skills in English are mandatory.
For further information about the PhD Program, and to apply through the online system, please visit:
What impact do the nuclear components of metabolism have on gene expression? And how does the distribution of metabolites contribute to the emergence of cancer? To answer those key questions, a Consolidator Grant of the European Research Council ERC was awarded to Stefan Kubicek, Principal Investigator at CeMM.
Genes need to be controlled. This very basic principle for a well-functioning cell – and thus a healthy organism – has been investigated thoroughly during the last decades. Huge progress in disciplines like epigenetics has revealed that in the cell´s nucleus various kinds of biomolecules are highly compartmentalized to occupy distinct regions of the chromatin – the material chromosomes are made of – and contribute to the regulation of genes. In contrast, small molecules and cellular metabolites are generally considered to lack a distinct subnuclear localization and not directly influence gene expression.
This assumption is challenged by Stefan Kubicek, Principal Investigator at CeMM: based on preliminary results from his laboratory, he hypothesizes that chromatin-bound enzymes of central metabolism and subnuclear metabolite gradients contribute to gene regulation and cellular identity – and also to the emergence of cancer. To address this hypothesis, Stefan Kubicek was awarded with a ERC consolidator grant with the project title “chromabolism” (from chromatin and metabolism) worth ~2 Million Euro.
Stefan Kubicek studied organic chemistry in Vienna and Zürich. He received his Ph.D. in Thomas Jenuwein’s group at the IMP in Vienna followed by postdoctoral work with Stuart Schreiber at the Broad Institute of Harvard and MIT in the U.S. He joined CeMM in 2010, and is also head of the Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives.
Principal Investigators at CeMM so far received 2 ERC Advanced Investigator Grants, 4 ERC Starting Grants and 2 Proof of Concept Grants. Stefan Kubicek is now awarded with CeMM’s first ERC Consolidator Grant. ERC Consolidator Grants are designed to support excellent Principal Investigators at the career stage at which they may still be consolidating their own independent research team or programme. Applicant Principal Investigators must demonstrate the ground-breaking nature, ambition and feasibility of their scientific proposal. Consolidator Grants may be awarded up to a maximum of 2 Million Euro for a period of 5 years. erc.europa.eu/funding/consolidator-grants