A new computer model reveals mechanisms of blood stem cell regulation and leukaemia development
Blood stem and progenitor cells replenish a person’s entire blood system throughout their life and are crucial for survival. These cells have the potential to become any type of blood cell, including white blood cells and red blood cells. It is important to understand how the balance of cell types is maintained because in cancers of the blood (also known as leukaemias) this organisation is lost and some cells proliferate abnormally.
Almost all of a person’s cells will contain the same genetic information, but different cell types arise when different genes are switched on or off. The genes encoding proteins called transcription factors are particularly important because the proteins can control – either by activating or repressing – many other genes. Importantly, some of these genes will encode other transcription factors, meaning that these proteins essentially work together in networks.
Schütte et al. have now combined extensive biochemical experiments with computational modelling to study some of the transcription factors that define blood stem / progenitor cells in mice. Firstly, nine transcription factors, which were already known to be important in blood stem cells, were thoroughly studied in mouse cells that could be grown in the laboratory. These experiments provided a global view of which other genes these transcription factors control. Additional targeted investigations of the nine transcription factors revealed how they act in combination to activate or repress their respective activities. With this information, Schütte et al. built a computational model, which accurately reproduced how real mouse blood stem/progenitor cells behave when, for example, a transcription factor is deleted. Furthermore, the model could also predict what happens in single cells if the amounts of transcription factors change.
Lastly, Schütte et al. studied a common type of leukaemia. The model showed that the mutations that occur in this cancer change the finely tuned balance of the nine transcription factors; this may explain why leukaemia cells behave abnormally. In future these models could be extended to more transcription factors and other cell types and cancers.
Full article in eLife
Schütte J, Wang H, Antoniou S, Jarratt A, Wilson NK, Riepsaame J, Calero-Nieto FJ2, Moignard V, Basilico S, Kinston SJ, Hannah RL, Chan MC, Nürnberg ST, Ouwehand WH, Bonzanni N, de Bruijn MF, Göttgens B. An experimentally validated network of nine haematopoietic transcription factors reveals mechanisms of cell state stability. Elife. 2016 Feb 22;5. pii: e11469. PMID: PMID: 26901438