Introduction
Hematopoietic Stem Cells (HSCs) possess the unique attributes of self-renewal and multipotency, which enable the healthy generation of blood and immune cells. HSCs might also be the source for hematologic malignancies. Stress-hematopoiesis, such as infection and inflammation, is suggested to increase the risk of pre-malignancy and leukemia. However, the mechanisms via which stress mediates transformation is unclear, and there is a lack of models with which to interrogate this phenomenon. Revealing how stress-hematopoiesis is skewing HSCs towards malignancy will suggest new ways to modulate pre-malignant state and minimize the risk of blood cancers.
Materials and Methods
Mice with a mutant p53 allele (R172H, equal to R175H in humans) are challenged by repeated induction of interferons. Protocol includes four weeks of serial injection with pIpC followed by a four-week recovery period, that repeat up to 3 times.
BBone marrow spleen, thymic, and lymph node cells are stained for lymphoid and myeloid progeny and stem- and progenitors. FACS cytoflex is used for analysis and cytexpert analysis software was used to analyze FACS data.
Results
Despite clear changes during stimulation, we find little impact of the chronic long-term immune stimulation on most hematological parameters regardless of the status of p53 (wt and mutant p53 allele). However, mice with a mutant p53 allele treated with pIpC exhibited a large spleen, thymus, and lymph nodes. We observed the increased frequencies of CD8+ T cells but not CD4+ T cells in p53MUT mice, following chronic pIpC. In these experiments, p53MUT developed lymphoma while WT did not develop such malignancy during same time.
Conclusion
Our data suggest little direct-damage to HSCs by the parameter tested so far, and a profound malignancy in the p53MUT mice following chronic stimulation. Hence, cancerous impact of stress hematopoiesis might drive malignancy at different levels of the hematopoietic system.