The MHH joint project TARGET-MPN is investigating why myeloproliferative neoplasms (MPN) evade targeted therapy and develop into leukaemias.
Focusing on the signalling pathways: Professor Dr Florian Heidel wants to find out why blood stem cell clones evade targeted treatment and develop into leukaemias. Copyright: Karin Kaiser / MHH
Haematopoietic stem cells supply us with fresh blood throughout our lives and ensure that our immune system functions properly. In adults, haematopoietic stem cells are found in the bone marrow. There they divide and develop into new mature blood cells such as red and white blood cells or platelets. Normally, this process is strictly regulated. However, in myeloproliferative neoplasia (MPN), a group of malignant bone marrow diseases, the process gets out of control due to mutations in the stem cells and blood cancer develops. MPNs mainly affect older people and are usually characterised by a slow progression. To date, there is no drug therapy that can prevent the progression of the disease. The only way out so far is a stem cell transplant, but this is only indicated for patients with an advanced stage of the disease due to the risks involved.
A number of genetic changes have already been discovered that lead to the various MPN disease patterns and allow a more precise differentiation in the diagnosis. However, it is not yet known which overarching molecular mechanisms are responsible for MPN disease persisting or even progressing under treatment. The "TARGET-MPN" research group now wants to clarify this. Under the leadership of Professor Dr Florian Heidel, Director of the Department of Haematology, Haemostaseology, Oncology and Stem Cell Transplantation at Hannover Medical School (MHH), the researchers are looking for new approaches to prevent diseased cells from persisting and to halt the progression of the disease. The German Research Foundation is funding the multicentre joint project over four years with a total of 5.1 million euros, of which 1.5 million euros will go to MHH projects.
Spread of cell clones
The work at the MHH is focussing on the question of the influence of the cell environment and cell communication, i.e. the transmission of messages from one cell to another. "For example, we are looking at certain signalling pathways in the cells that are controlled by the enzyme JAK2," says Professor Heidel. JAK2 is involved in many processes of cell division and cell development. A specific mutation in the JAK2 gene ensures that the haematopoietic stem cells continue to divide and thus triggers MPN. The researchers want to investigate how the signalling pathways are altered in the course of disease development and which factors in the cell environment influence them directly or indirectly.
Mutations in haematopoietic stem cells occur at an early stage. In the course of life, the genetic composition of the cells changes and different cell clones are formed. As the haematopoietic system ages, these clones spread and can degenerate further, eventually leading to acute leukaemia. Epigenetic processes also play an important role in this process. They control which genes are switched on or off and which properties a cell has. "Epigenetics has an influence on whether and when an MPN disease progresses," explains Professor Heidel. "If we know which epigenetic regulators are involved in the growth of cell clones and their transformation into aggressive tumour cells, we can start there and prevent the disease from turning into aggressive leukaemia."
MPN case numbers will increase
According to the haematologist, the importance of MPN in cancer medicine will continue to increase. In Germany, it is already the fourth most common reason for an adult presentation to a haematologist or oncologist in private practice. And because the proportion of older people in the population will continue to rise as a result of demographic change, the number of cases of this age-related disease will also increase.
In addition to the Department of Haematology, Haemostaseology, Oncology and Stem Cell Transplantation, which is part of the MHH Comprehensive Cancer Centre (CCC), the following institutions are involved in the research group: Freiburg University Hospital, Charité Universitätsmedizin Berlin, Ulm University Hospital, the German Cancer Research Centre in Heidelberg, Halle/Saale University Hospital, RWTH Aachen University and, in Austria, Paris Lodron University in Salzburg and Graz University Hospital.
Text: Kirsten Pötzke