Mutant P53 Promotes Clonal Hematopoiesis By Generating A Chronic Inflammatory Microenvironment
Our bodies constantly produce new blood cells from special “master” cells called hematopoietic stem and progenitor cells (HSPCs). As we age, some of these cells can acquire mutations, leading to a condition known as clonal hematopoiesis (CH), where a single mutated cell type starts to dominate. Individuals with CH, especially those with mutations in a gene called TP53, face a higher risk of developing serious blood cancers like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
This research sheds light on how a mutated TP53 gene contributes to this process. It turns out that when TP53 is mutated in HSPCs, it causes these cells to create a constant state of inflammation in the bone marrow, which is where blood cells are made. This inflammatory environment is harmful to normal, healthy HSPCs, essentially giving the mutated cells a competitive edge and allowing them to multiply and expand.
The study found that the mutant TP53 gene interferes with how genetic instructions are processed in HSPCs, leading to increased activity of a pathway called NF-κB and a higher release of inflammatory signaling molecules, such as IL-1β and IL-6. This chronic inflammation then suppresses the growth and function of healthy blood stem cells.
Crucially, the findings suggest potential new ways to intervene. By blocking IL-1β, one of the key inflammatory molecules, or by inhibiting a protein called gasdermin D (GSDMD) which is involved in its release, the competitive advantage of the mutant cells was reduced. This indicates that targeting inflammation could be a promising strategy to prevent the progression of CH with TP53 mutations to more aggressive blood cancers.
Source: link to paper