Signal transmission mechanism in blood cell development deciphered

An international research team involving partners from Germany, United Kingdom, Finland and the USA has achieved a fundamental breakthrough in understanding the mechanism of the development of new blood cells and its role to get out of control in leukaemias.

The results of the research project were published on February 7 in the new issue of the renowned journal "Science", said a press release issued by the University of Helsinki.

In adults, billions of mature blood cells are formed from haematopoietic stem cells in the bone marrow every day.

This process is tightly regulated by a family of messenger proteins called cytokines that control the development and proliferation of the different blood cell types.

Cytokines interact with specific receptors on the surface of cells, which allows the transmission of signals controlling whether the cell divides or differentiates into a specific blood cell type.

Various leukaemias are associated with genetic mutations that activate these signalling pathways in the absence of cytokines in an uncontrolled manner. Until now, the molecular mechanisms of how individual mutations trigger signal activation and lead to these blood cancers have remained unclear.

“By directly visualising individual receptors at physiological conditions under the microscope, we were able to resolve a controversy that has preoccupied the field for more than 20 years," said Professor Jacob Piehler from Osnabrück University.

In combination with biomedical studies at the Universities of York and Dundee, the researchers found that several important disease-relevant mutations led to the pairing of certain receptors without cytokine.

"These observations led us to a previously unknown mechanism how individual mutations at this receptor trigger cytokine-independent signalling and thus can promote leukaemia," said Professor Ian Hitchcock from the University of York.

Cooperation partners at the University of Helsinki used these insights to develop a comprehensive structural model via atomic-scale simulations and molecular modelling, which could explain the different modes of action of different mutations.

"Our biomolecular simulations unveiled surprising features concerning the orientation of active receptor pairs at the plasma membrane, explaining how mutations render activation possible without a ligand. These predictions were subsequently confirmed experimentally", explained Professor Ilpo Vattulainen from the University of Helsinki.

These fundamental insights into the mechanism of signal activation enable completely new and much more targeted strategies for combating leukaemias. Further, the researchers suspect that a wide range of inflammatory and allergic diseases can also be traced back to similar mechanisms.