Defining clonal hematopoiesis of indeterminate potential: evolutionary dynamics and detection under aging and inflammation.

Clonal hematopoiesis (CH), where hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer, and a greater likelihood of cardiovascular and pulmonary disease. Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. While CHIP does elevate the risk of eventual hematological malignancy, only one in ten individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a pre-malignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign. In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with potential for translational applications and clinical utility in the near future.