The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

Abstract

Aberrations in the p53 tumor suppressor pathway are associated with hematologic malignancies. p53-dependent cell cycle control, senescence, and apoptosis functions are actively involved in maintaining hematopoietic homeostasis under normal and stress conditions. Whereas loss of p53 function promotes leukemia and lymphoma development in humans and mice, increased p53 activity inhibits hematopoietic stem cell function and results in myelodysplasia. Thus, exquisite regulation of p53 activity is critical for homeostasis. Most of our understanding of p53 function in hematopoiesis is derived from genetically engineered mice. Here we summarize some of these models, the various mechanisms that disrupt the regulation of p53 activity, and their relevance to human disease.

Figure 1

Role of p53 in HSCs. A simplistic model depicting changes in p53 levels during differentiation of HSCs into the lineage components (left). p53 activity levels influence HSC functionality (right).

Figure 2

p53 regulates HSC quiescence. (A) Under homeostatic conditions, p53 regulates HSC quiescence mediated by Gfi-1 and Necdin and maintains HSC self-renewal by an unknown mechanism. (B) Under stress conditions, enhanced p53 activity promotes transcription of downstream targets, which trigger cell cycle arrest, senescence, or apoptosis. p53 also transactivates Pig genes, which induce ROS levels and promote p53 stability.