€2.45 m to investigate leukaemia causes and therapies
The Heidelberg-based LeukoSyStem consortium investigates leukaemia stem cells in acute myeloid leukaemia. The German Federal Ministry of Education and Research financially supports this collaboration between Heidelberg University Hospital, HI-STEM gGmbH, the German Cancer Research Center and EMBL.
Leukaemia stem cells are considered to be the starting point of leukaemia; their elimination is a basic prerequisite for a successful long-term therapy. Scientists at Heidelberg University Hospital (UKHD), the Heidelberg Institute for Stem Cell Technology and Experimental Medicine at the German Cancer Research Center (HI-STEM/DKFZ), the German Cancer Research Center (DKFZ) and the European Molecular Biology Laboratory (EMBL) have now obtained research funding of €2.45 million from the German Federal Ministry of Education and Research (BMBF) as part of the junior research alliance LeukoSyStem. The aim of their project is to investigate the cells that are the origin of acute myeloid leukaemia (AML) and thus “get to the root of the problem”. The scientists intend to use isolated single cells from patient samples to investigate characteristic markers, mutations, functional data, and metabolic pathways, to gain a better understanding of leukaemia stem cells and their environment in bone marrow. The collected data will be evaluated comprehensively with the help of computer algorithms specially developed for the purpose.
Leukemia stem cells as the origin of a disease that is often fatal
The development of normal, healthy blood cells starts from haematopoietic stem cells in the bone marrow and proceeds through various stages of so-called precursor cells. In each of these stages, the accumulation of mutations can lead to cell degeneration and the development of blood cancer (leukaemia).
Acute myeloid leukaemia (AML) is the most common form of leukaemia in adults. In AML, mutated, functionless blood cells – known as blasts – overgrow other bone marrow cells. Every year in Europe, three to five out of every 100 000 people receive a diagnosis of AML. Despite therapeutic options such as chemotherapy and stem cell transplantation, relapses are frequent and the five-year survival rate for patients up to the age of 60 is 35–40%. For patients above 60, it is only 5–10%.
A basic prerequisite for the effective cure of patients is the targeted elimination of the leukaemia’s starting cells, called leukaemia stem cells. “For therapy, we need to find the cause of the problem and tackle the leukaemia stem cells,” says Dr. med. Simon Raffel, project partner from the Department of Haematology, Oncology and Rheumatology (Medical Director: Prof. Dr. Carsten Müller-Tidow) at UKHD. Like healthy stem cells, leukaemia stem cells are located in the stem cell niche in the bone marrow and are able to constantly produce new leukaemia cells (blasts). The interaction of leukaemia stem cells with other factors and cells of the stem cell niche is not yet fully understood. This is where the currently approved junior research alliance comes in, which comprises three sub-projects: the analysis of single leukaemia stem cells, an investigation of the stem cell niche in the bone marrow, and a systems medical, comprehensive evaluation of the collected data.
In the stem cell niche, healthy and non-functional blood cells thrive equally
Dr. Simon Raffel from UKHD, in cooperation with Dr. Lars Velten of the Centre for Genomic Regulation (CRG), in Barcelona, Spain, will investigate the characteristics of leukaemia stem cells of AML patients in comparison with healthy blood cells. For this purpose, patient cells are isolated and surface markers, specific mutations, cell functions, and special metabolic properties of diseased cells are compared to healthy cells.
The leukaemia stem cells are located in the patient’s bone marrow – in the stem cell niche – which contains a diverse range of cells, such as immune, blood vessel, and connective tissue cells. To investigate their contribution to the development of leukaemia and resistance to therapy, the project coordinator and project leader Dr. Simon Haas (HI-STEM/DKFZ) will develop novel single-cell and spatially resolved analysis methods and use them to systematically investigate the AML microenvironment. “With our work, we hope to gain a better understanding of the pathogenesis and therapy resistance mechanisms of AML as a whole, which in the medium term will lead to new diagnostic and therapeutic options,” says Simon Haas.
In the third sub-project, the data collected using different methods will be evaluated by physicist and mathematician Dr. Laleh Haghverdi from EMBL. She will develop new bioinformatics methods and algorithms for integration and analysis in a systems biology approach. “Previous studies have looked at individual aspects of leukaemia cells, be they DNA mutations, RNA, or metabolic factors. We are now specifically aiming to use a comprehensive approach to investigate the interaction of multiple aspects of AML,” she explains.
Fighting leukemia cells, sparing healthy cells
The researchers are particularly interested in being able to better distinguish between healthy and leukaemia stem cells, as this is only possible to a limited extent using existing markers. Only when this can be done more precisely can new biomarkers for the discovery of the mutated cells be identified, opening up possible new points of attack for targeted therapies. “The treatment of AML will be all the more successful the more precisely we can specifically eliminate the leukaemia’s starting cells and spare the healthy blood cells in the future,” says Simon Raffel.
The funding of the junior research alliance LeukoSyStem by the German Federal Ministry of Education and Research (BMBF) enables the young scientists from Heidelberg to carry out interdisciplinary research in systems medicine. The project started at the beginning of 2020. The total funding amounts to approximately €2.45 million over five years, with a share of approximately €1.3 million for the Department of Haematology, Oncology and Rheumatology at UKHD.
The development of
normal, healthy blood cells starts from haematopoietic stem cells in the bone
marrow and proceeds through various stages of so-called precursor cells. In
each of these stages, the accumulation of mutations can lead to cell
degeneration and the development of blood cancer (leukaemia).