Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and partners in Hungary have studied the response to targeted leukemia therapy in unprecedented detail, using single-cell sequencing and epigenetic analysis. The paper published in the journal Nature Communications uncovers a precise molecular program in patients with chronic lymphocytic leukemia (CLL) who start treatment with the targeted cancer drug ibrutinib. While this program was shared by all patients, the speed of its execution differed widely. These results will help develop personalized strategies for managing CLL as a chronic disease.
Chronic lymphocytic leukemia (CLL) is the most common form of blood cancer (leukemia) in the Western world, affecting approximately 1.2% of all cancer patients. This type of cancer starts with the lymphocytes (a type of white blood cells) that are produced in the bone marrow. CLL is characterized by the proliferation of abnormal lymphocytes (B cells) that fail to mature and grow out of control.
Leukemia cells are depicted in green, normal blood cells in red, and the intricate bundles in each cell visualize the complex arrangement of DNA and chromatin in the cell nucleus.
These abnormal cells accumulate in the bone marrow and lymph nodes, taking the place of other healthy cell types and impeding their normal development. Finding the most suitable therapy for each patient poses a challenge due to the clinical and molecular heterogeneity of this disease, with some patients facing slow disease progression, whereas others face rapid progression and require quick medical response.
The cancer drug ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has remarkable efficacy in most patients with CLL. It is becoming the standard of care for most patients requiring treatment due to its clinical efficacy and mostly tolerable side effects. However, it does not cure the disease, and patients must undergo prolonged periods of treatment. Christoph Bock and his group at CeMM investigated the molecular program with which CLL cells and other immune cells response to ibrutinib treatment in patients with CLL. Their goal was to learn the epigenetic and transcriptional patterns that predict how swiftly the treatment is having an effect on the CLL cells and how long it takes for the disease to respond in each individual patient.
In previous studies, scientists had investigated only specific aspects of the molecular response to ibrutinib, focusing largely on genetic drug resistance or the transcriptome response of cancer cells. For the first time, CeMM researchers provide a comprehensive genome-scale, time-resolved analysis of the regulatory response to this drug in primary patient samples. The authors used a combination of immunophenotyping, single-cell transcriptome profiling (scRNA-seq) and chromatin mapping (ATAC-seq) to jointly monitor the activity, regulation and expression of the CLL cells and other cell types of the immune system. Importantly, they performed this analysis at eight pre-defined time points during the ibrutinib therapy, following seven individual patients over a standardized 240-day period after the start of the treatment.
Through integrative bioinformatic analysis of the resulting dataset, the authors were able to describe at high resolution how ibrutinib induces a very consistent chain of events on cancer cells over time across all patients. They found that ibrutinib first acts right at the center of the CLL cells’ activity, causing the genes that establish the cancer cell identity of the CLL cells to shut down, and then puts them in a dormant state. This means that the cancer cells stop dividing but quiescently survive, waiting for the right environment conditions to begin proliferation once again.
The present study by André Rendeiro, Thomas Krausgruber and colleagues is the result of cross-disciplinary collaborations with researchers from the Department of Hematology and Stem Cell Transplantation of the National Institute of Hematology and Infectious Diseases at the Central Hospital of Southern Pest, and the Department of Pathology and Experimental Cancer Research of the Semmelweis University in Budapest (Hungary). It constitutes one of the first high-resolution, multi-omics time series of the molecular response to targeted therapy in cancer patients, and it establishes a broadly applicable approach for analyzing drug-induced regulatory programs, identifying molecular response markers for targeted therapy. Finally, the study could help stratify patients into fast and slow responders based on characteristic molecular markers and open up new directions for the development of ibrutinib-based combination therapies for CLL.
“Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in chronic lymphocytic leukemia” was published in Nature Communications on 29 January 2020 DOI: 10.1038/s41467-019-14081-6
Laura Alvarez | idw - Informationsdienst Wissenschaft
Colorectal cancer: Increased life expectancy thanks to individualised therapies
20.02.2020 | Christian-Albrechts-Universität zu Kiel
Sweet beaks: What Galapagos finches and marine bacteria have in common
20.02.2020 | Max-Planck-Institut für Marine Mikrobiologie
The operational speed of semiconductors in various electronic and optoelectronic devices is limited to several gigahertz (a billion oscillations per second). This constrains the upper limit of the operational speed of computing. Now researchers from the Max Planck Institute for the Structure and Dynamics of Matter in Hamburg, Germany, and the Indian Institute of Technology in Bombay have explained how these processes can be sped up through the use of light waves and defected solid materials.
Light waves perform several hundred trillion oscillations per second. Hence, it is natural to envision employing light oscillations to drive the electronic...
Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.
Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...
Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices
The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...
Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.
Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.
After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.
"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.
12.02.2020 | Event News
16.01.2020 | Event News
15.01.2020 | Event News
21.02.2020 | Medical Engineering
21.02.2020 | Health and Medicine
21.02.2020 | Physics and Astronomy