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A new study published in Cell Stem Cell by the Vyas Group (MRC Molecular Haematology Unit), in collaboration with the Dick and Xie labs at Princess Margaret Cancer Centre (Toronto), sheds light on how common spontaneous DNA mutations may lead to the growth of a pre-cancerous condition in blood cells.
Every day we make billions of new blood cells. This enormous production of new cells is required to sustain our lives and is maintained by a rare subset of cells in the bone marrow called blood stem cells. As we age, most cells, including blood stem cells, acquire changes in their DNA (the code that helps instruct cells how to function).
Some of these DNA changes give blood stem cells an advantage that allows them to outcompete other blood stem cells, leading to a “clonal outgrowth” of cells that share the same mutation. This is common in healthy older people and can predispose them to the development of blood cancers and other diseases associated with inflammation, like heart attacks and stroke. This condition is called Clonal Haematopoiesis (CH).
CH usually begins in young or middle-aged individuals but largely goes unnoticed as the impact on blood cells is very subtle. As CH starts decades before the development of serious disease, there is potential to identify those at higher risk of disease before the onset of symptoms and potentially provide early treatment. However, it has been challenging to study this in humans, because most individuals with CH are clinically well, and do not undergo investigations of the bone marrow.
To address this, the Vyas Group collaborated with orthopaedic teams at the Botnar Institute for Musculoskeletal Sciences and the Nuffield Orthopaedic Centre to collect samples from a large group of healthy individuals undergoing hip replacement surgery. This way, they could identify individuals with CH and study the impact of the mutations on blood stem cells.
Most cases of CH are caused by mutations in two genes, called DNMT3A and TET2. To investigate how these mutations alter blood cell function, the research team used an improved single-cell technique, called TARGET-seq+, to detect these mutations and analyse gene activity in the same single cells. This way, the researchers were able to map out which cells gained a growth advantage and how the cells with the mutation differed from their normal counterparts.
This analysis revealed that most of the growth advantage caused by the DNMT3A and TET2 mutations occurred in blood stem cells. The research team discovered that these mutations may give stem cells a growth advantage by protecting them against the negative effects of inflammation and ageing. This could allow the mutated cells to gradually out-compete their non-mutated counterparts.
Asger Jakobsen, one of the paper's joint first authors, said:
This was the first detailed analysis of CH in human blood stem cells. It provides a foundation for understanding how mutations lead to a growth advantage, suggesting potential avenues that may be exploited therapeutically to reduce the risk of disease.
Read the full paper here: https://doi.org/10.1016/j.stem.2024.05.010