Clonal hematopoiesis is common in older persons and is associated with an increased risk of hematologic cancer. Here, we review studies establishing an association between clonal hematopoiesis and hematopoietic malignancy, discuss features of clonal hematopoiesis that are predictive of leukemic progression, and explore the role of hematopoietic stressors in the evolution of clonal hematopoiesis to acute myeloid leukemia or myelodysplastic syndrome. Clonal hematopoiesis due to point mutations or structural variants, such as copy number alterations, are associated with an approximately 10-fold increased risk of hematopoietic malignancy. Although the absolute risk of hematopoietic malignancy is low, certain features of clonal hematopoiesis may confer a higher risk of transformation, including the presence of TP53 or splicesome gene mutations, a variant allele fraction greater than 10%, the presence of multiple mutations, and altered red blood indices. Clonal hematopoiesis in the setting of peripheral blood cytopenias carries a very high risk of progression to a myeloid malignancy and merits close observation. There is emerging evidence to suggest the hematopoietic stressors contribute both to the development of clonal hematopoiesis and progression to hematopoietic malignancy. Specifically, there is evidence that genotoxic stress from chemotherapy or radiation therapy, ribosome biogenesis stress, and possibly inflammation may increase the risk of transformation from clonal hematopoiesis to a myeloid malignancy. Models that incorporate features of clonal hematopoiesis along with an assessment of hematopoietic stressors may eventually help predict and prevent the development of hematopoietic malignancies.

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