TP53 (tumour protein 53) is the most frequently mutated gene in human cancers. In this study published in Nature Genetics and led by Dr Alba Rodriguez-Meira, Professor Adam Mead (MRC MHU) and Dr Iléana Antony-Debré (Inserm), the authors investigated the link between an aggressive type of leukaemia and TP53 mutations in haematopoietic stem cells.
Haematopoietic stem cells (HSCs) can differentiate to produce all blood cell types, which is essential for maintaining a healthy blood system. TP53 mutations in HSCs have previously been associated with a cancer progression pathway that leads to the development of acute myeloid leukaemia. Up until now, the mechanisms by which these TP53-mutated blood stem cells expand and give rise to cancer have remained in the dark.
Haematopoietic Stem Cells and Inflammation
Under normal circumstances, HSCs will differentiate into white blood cells when the body senses inflammation and the white blood cells produced will help to fight the infection. However, this study showed that, in patients with TP53 mutations in their HSCs, inflammation gave rise to selective expansion of TP53-mutant cells, which cannot differentiate normally.
TP53 is also known as the “guardian of the genome” because it ensures that cells don’t carry genetic errors; if they do, TP53 activates a process called programmed cell death and prevents the expansion of damaged stem cells. However, in patients where TP53 is defective, stem cells cannot keep their genomic integrity. In this context, inflammation acts as a storm that depletes normal HSCs from bone marrow, while promoting the expansion of TP53-mutant cells. This eventually leads to an aggressive type of cancer.
Overall, these findings offer valuable insights into how genetic defects and inflammation interact in the development of blood cancer. Importantly, this study could pave the way for better methods of early detection and new treatments for TP53-mutant leukaemia and many other cancer types, improving outcomes for cancer patients. - Dr Alba Rodriguez-Meira, one of the paper’s co-first authors
I am really proud of this work which illustrates how cutting-edge single-cell techniques can provide novel insights into human disease. The connection between inflammation and genetic evolution in cancer has broad implications and the challenge is now to determine how we might intervene in this process to more effectively treat, or even prevent the inflammation associated with cancer progression. I would like to thank the patients who donated samples to support this research at a very difficult time in their lives and also all coauthors and our funders, particularly CRUK and MRC. - Professor Adam Mead