| Popis: |
Hematopoietic stem and progenitor cells (HSPCs) can acquire age-dependent somatic mutations that result in clonal expansion, a process termed clonal hematopoiesis, presumably as a consequence of a competitive fitness advantage in the setting of an aging HSPC pool. Genetic analyses of large population cohorts have demonstrated consistently that clonal hematopoiesis is detectable in the blood of subjects without a clinically apparent myeloid neoplasm. The prevalence of clonal hematopoiesis increases with age and genes that are commonly mutated in clonal hematopoiesis and are also recurrently mutated in myeloid malignancies. The presence of clonal hematopoiesis is associated with an increased risk of developing a hematologic malignancy, increased risk of cardiovascular disease, and a higher all-cause mortality rate. However, only a fraction of individuals with age-dependent clonal hematopoiesis develop a myeloid malignancy; thus, the term “clonal hematopoiesis of indeterminate potential” (CHIP) has been suggested to describe the acquisition of somatic mutations associated with clonal expansion without evidence of hematologic disease. Mutations in the epigenetic modifiers DNMT3A, TET2, and ASXL1 account for the majority of age-dependent clonal hematopoiesis. Individuals with clonal hematopoiesis and the presence of a cytopenia are at a particularly increased risk of developing a subsequent hematologic malignancy. However, the size of a CHIP clone can remain stable over time, and most individuals harboring mutations do not progress to a myeloid neoplasm. This suggests that clonal evolution through the acquisition of cooperating mutations and/or selection of mutant HSPCs by stressors that promote the expansion of cells with a fitness advantage is required for progression. Clonal hematopoiesis can occur after treatment with cytotoxic chemotherapy and is associated with TP53 mutations and an increased risk of developing a therapy-related myeloid neoplasm. Future studies of the natural history of CHIP and strategies to identify at-risk individuals, coupled with an intervention strategy to prevent subsequent development of hematologic malignancies, are needed. |
