New Insights from Studies of Clonal Hematopoiesis

Clonal hematopoiesis (CH) describes an asymptomatic expansion of blood cells descended from a single hematopoietic stem cell. Recent studies have shown that CH increases in frequency with aging and is often driven by somatic mutations in genes that are recurrently mutated in hematologic malignancies. When CH is associated with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or greater it is termed clonal hematopoiesis of indeterminate potential' (CHIP). CHIP has a 0.5% to 1% risk per year of progression to hematologic neoplasia, arid increases both all-cause mortality and the risk of myocardial infarction and ischemic stroke due to a proinflammatoiy interaction between clonally derived leukocytes and vascular endothelium. CH frequently emerges in the context of immune-mediated marrow failure syndromes such as aplastic anemia, whereas CH emerging after cytotoxic cancer therapy is strongly associated with subsequent development of a therapy-related myeloid neoplasm, especially if a TP53 mutation is present. However, risk factors for developing CH other than aging, marrow failure, and cytotoxic radiotherapy or chemo therapy are poorly defined. In this review, we discuss the epidemiology, molecular mechanisms, and clinical consequences of this common and clinically important biological state.