Mutated blood stem cell receptors could be therapeutic targets for leukaemia

Researchers have identified that in leukaemia, mutated receptors allow blood stem cells to activate one another without the proper signal and suggest this discovery could lead to targeted novel therapies.

blood vessel with few red blood cells and many white blood cells, indicating leukaemia

Research into cell signalling has shown that in leukaemia, mutations in the cytokine receptors of blood stem cells triggers an overproduction of blood cells, causing the condition. The scientists hope this discovery will pave the way for targeted novel therapeutics in future.

In the study, published in Science, the research team discovered that while blood stem cells are normally regulated by cytokines, mutations can allow them to be activated without the correct signals, prompting the development of blood cells to spiral out of control.

The researchers used super-resolution fluorescent microscopy to study the way blood stem cells communicate with each other in real time. They observed cytokines binding to designated cell surface receptors, pairing the blood stem cells up and causing the production of blood cells. But when cells with mutations affecting these receptors were introduced, the cells paired up without cytokines and produced an imbalance of healthy platelets, white and red blood cells.

Professor Ian Hitchcock from the York Biomedical Research Institute and the Department of Biology at the University of York, UK, explained: “Our bodies produce billions of blood cells every day via a process of cells signalling between each other. Cytokines act like a factory supervisor, tightly regulating this process and controlling the development and proliferation of the different blood cell types.

“Our observations led us to a previously unknown mechanism for how individual mutations trigger blood stem cells to start signalling independently of cytokines, causing the normal system to become out of control and leading to diseases like leukaemia. Understanding this mechanism may enable the identification of targets for the development of new drugs.”

Professor Ilpo Vattulainen from the University of Helsinki, Finland, added: “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 (eg, cytokine). These predictions were subsequently confirmed experimentally.”