Penny Min
Published September 15, 2023
In blood stem cells with p53 mutations — the so-called “guardian of the genome” — research has uncovered hitherto unrecognized impacts of persistent inflammation on the emergence of cancer.
The protein p53, generated by the gene TP53, is regarded as “the guardian of the genome,” according to research published in Nature Genetics. Apoptosis, a process by which cells “self-destruct” to stop themselves from procreating additional damaged cells, is triggered when p53 is activated. However, mutations can make p53 ineffective, which allows injured cells to continue dividing unchecked.
As many as 50% to 60% of human malignancies have a TP53 mutation, which can result in cancer development. Hematopoietic stem cells (HSCs) with TP53 mutations have been associated with acute myeloid leukemia (AML), an aggressive kind of blood cancer.
By creating all different types of blood cells, they are in charge of preserving a healthy blood system. The processes behind how these mutant HSCs multiply to produce cancer were largely unknown. In the current study, researchers from the University of Oxford examined how chronic inflammation affects TP53-mutant HSCs in cancer development.
The study team used TARGET-seq, a single-cell method, to examine the impact of the mutation. This enabled them to use cells provided by individuals with myeloproliferative neoplasms, a condition that predisposes them to leukemia, to explore how TP53 mutations in HSCs impact cancer progression.
What did the results entail?
Researchers discovered that cells from individuals with TP53 mutations exhibited higher levels of inflammation-related gene activation. They established, using laboratory mice, that these mutant cells multiplied when the animals were exposed to inflammatory stimuli.
Additionally, compared to healthy HSCs, the mutant HSCs generated fewer white blood cells and were more resistant to cell death, which is normally brought on by inflammation. This indicates that compared to non-mutant HSCs, the mutated HSCs were better able to grow when exposed to inflammation and were more “fit” to survive.
The inability of TP53-mutated cells to effectively repair mistakes in their genetic coding when subjected to inflammation may exacerbate this impact and aid in cancer growth.
“Overall, these findings offer valuable insights into how genetic defects and inflammation interact in the development of blood cancer.”
– Co-first author Alba Rodriguez-Meira
Additionally, she continues that this research may lead to novel approaches for TP53-mutant leukemia therapy and other cancer types, improving results for cancer patients.
The connection between inflammation and genetic evolution in cancer has broad implications, says senior author Adam Mead. The challenge is to figure out how scientists might intervene in this process to treat or prevent the inflammation linked to cancer progression more effectively.