Role of p53 in regulation of hematopoiesis in health and disease

Abstract

Purpose of review: Human aging is associated with an exponential increase in the occurrence of clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with increased risks of de novo and therapy-related hematologic neoplasms and serves as a reservoir for leukemic relapse. Somatic mutations in the TP53 gene, which encodes the tumor suppressor protein p53, rank in the top five among genes that were mutated in CHIP. TP53 mutations in CHIP are associated with an increased incidence of myeloid neoplasms such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This review focuses on mechanisms by which mutant p53 promotes CHIP progression and drives the pathogenesis of MDS and AML. We will also discuss potential therapeutic approaches that can target mutant p53 and improve treatment outcomes of MDS and AML.

Recent findings: TP53 was frequently mutated in individuals with CHIP as well as in patients with MDS and AML. While clinical studies suggest that p53 mutant hematopoietic stem and progenitor cell expansion may predispose the elderly to hematologic neoplasms, the underlying mechanisms are not fully understood. Recent findings suggest that mutant p53 may utilize both cell autonomous and noncell autonomous mechanisms to promote CHIP development. Furthermore, we and others have demonstrated that several gain-of-function mutant p53 proteins have enhanced oncogenic potential beyond dominant-negative and loss-of-function effects. Notably, TP53 allelic state has important implications for genome stability, clinical presentation, and outcomes in MDS. Some small molecules reactivating wild-type p53 tumor suppressor activity show promising effects on some human MDS and AML cells with TP53 mutations in preclinical and early phases of clinical studies.

Summary: TP53 mutations in MDS and AML are correlated with advanced disease, poor prognosis, reduced overall survival, and dismal outcomes. Deep understanding of the functions of mutant p53 proteins is essential to devise effective therapies for patients with myeloid neoplasms and other human cancers with TP53 mutations. Targeting mutant p53 directly or pathways regulated by mutant p53 holds great potential in preventing CHIP progression and treating MDS and AML patients with TP53 mutations.