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Link Between Inflammation and Leukemia Development Identified

Computer-generated image of cancer cells.
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Research has revealed previously unknown effects of chronic inflammation on cancer development in blood stem cells with mutations in p53, the so-called “guardian of the genome”. The research is published in Nature Genetics.

Mechanisms underlying AML development

The protein p53, produced from the gene TP53, is known as “the guardian of the genome”. Activation of p53 can occur when cells accumulate genetic errors, triggering the cells’ “self-destruct” system – called apoptosis – to prevent them from giving rise to more damaged cells.

However, p53 can become defective as a result of mutations, meaning damaged cells can continue to divide unchecked. This can lead to the development of cancer, with approximately 50–60% of human cancers carrying a TP53 mutation.

Acute myeloid leukemia, or AML – an aggressive form of blood cancer – has been linked to TP53 mutations in hematopoietic stem cells (HSCs). These are responsible for maintaining a healthy blood system by producing all blood cell types.

Relatively little was known about the mechanisms underlying how these mutated HSCs expand to cause cancer. In the current study researchers from the University of Oxford explored how chronic inflammation has a previously unknown effect on TP53-mutant HSCs in cancer development.

Inflammation’s influence

The research team studied the effects of the mutation using a single-cell technique called TARGET-seq. This allowed them to study  how TP53 mutations in HSCs affect cancer progression using cells donated by patients with myeloproliferative neoplasms – a disease that predisposes them to leukemia.

The researchers found that patients’ TP53-mutated cells had increased activation of genes linked to inflammation. Using experimental mice, they confirmed that these mutated cells grew in number when the animals were subjected to inflammatory stimuli.

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The mutated HSCs also produced fewer white blood cells compared to healthy HSCs and were more resistant to cell death – a process typically brought about by inflammation. This means that the mutated HSCs were more “fit” to survive and were able to better able to expand when exposed to inflammation than non-mutant HSCs.

When exposed to inflammation,  TP53-mutated cells were also unable to repair errors in their genetic code as efficiently, potentially exacerbating this effect and contributing to cancer development.

Research has “broad implications”

“Overall, these findings offer valuable insights into how genetic defects and inflammation interact in the development of blood cancer,” said Dr. Alba Rodriguez-Meira, co-first author of the study and now a postdoctoral fellow at Dana-Farber Cancer Institute and Harvard Medical School. “Importantly, this study could pave the way for better methods of early detection and new treatments for TP53-mutant leukemia and many other cancer types, improving outcomes for cancer patients.”

“I am really proud of this work which illustrates how cutting-edge single-cell techniques can provide novel insights into human disease,” added Prof. Adam Mead, senior author of the study and professor of hematology at the University of Oxford. “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.”

Reference: Rodriguez-Meira A, Norfo R, Wen S, et al. Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution. Nat Genet. 2023;55(9):1531-1541. doi: 10.1038/s41588-023-01480-1

This article is a rework of a press release issued by the University of Oxford. Material has been edited for length and content.