Browsing by Subject "clonal hematopoiesis of indeterminate potential"

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    p53 involvement in clonal hematopoiesis of indeterminate potential
    (Wolters Kluwer, 2019-05) Chen, Sisi; Liu, Yan; Pediatrics, School of Medicine
    Purpose of review Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and occurs when a single mutant hematopoietic stem cell (HSC) contributes to a significant clonal proportion of mature blood lineages. 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. This review focuses on mechanisms by which mutant p53 promotes CHIP progression and drives the pathogenesis of hematological malignancies, including myelodysplastic syndromes, and acute myeloid leukemia. Recent findings TP53 was frequently mutated in individuals with CHIP. Although clinical studies suggest that expansion of HSCs with TP53 mutations predisposes the elderly to hematological neoplasms, there is a significant gap in knowledge regarding the mechanisms by which TP53 mutations promote HSC expansion. Recent findings suggest that several cellular stressors, including hematopoietic transplantation, genotoxic stress, and inflammation, promote the expansion of HSCs with TP53 mutations. Further, TP53 mutations identified in CHIP cooperate with genetic and/or epigenetic changes in leukemogenesis. Summary TP53 mutations identified in CHIP are associated with increased risks of de novo and therapy-related hematological neoplasms. Thus, targeting mutant p53 and related pathways holds great potential in preventing CHIP progression and treating hematological malignancies.
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    Putative Mechanisms Underlying Cardiovascular Disease Associated with Clonal Hematopoiesis of Indeterminate Potential
    (Elsevier, 2020-08-11) Burns, Sarah S.; Kapur, Reuben; Pediatrics, School of Medicine
    Characterized by the expansion of somatic mutations in the hematopoietic lineages of aging individuals, clonal hematopoiesis of indeterminate potential (CHIP) is a common condition that increases the risk of developing hematological malignancies and cardiovascular disease (CVD). The presence of CHIP-associated mutations in hematopoietic stem and progenitor cells (HSPCs) suggests that these mutations may alter the functions of the diverse hematopoietic lineages, many of which influence the pathogenesis of CVD. Inflammation may be a potential pathogenic mechanism, linking both CVD and hematological malignancy. However, it remains unknown whether CHIP-associated CVD and hematological malignancy are features of a common disease spectrum. The contributions of CHIP-associated mutations to both CVD and hematological malignancy underscore the importance of stem cell biology in pathogenesis and treatment. This review discusses possible mechanisms underlying the contributions of multiple hematopoietic lineages to CHIP-associated CVD and the putative pathogenic links between CHIP-associated CVD and hematological malignancy.