Clonal Hematopoiesis and VEXAS: Survival of the fittest clones?

Abstract Clonal hematopoiesis (CH) is defined by the acquisition of somatic mutations in hematopoietic stem cells (HSC) leading to enhanced cellular fitness and proliferation under positive clonal selection pressures. CH most frequently involves epigenetic regulator genes (DNMT3A, TET2 and ASXL1), with these mutations being associated with enhanced inflammation and increased all-cause mortality largely from cardiovascular disease and endothelial dysfunction. These mutations also increase the risk for hematological neoplasms. Somatic mutations in UBA1, encoding the E1 ubiquitin ligase in HSC, cause a severe adult-onset autoinflammatory disease that can be associated with myeloid and plasma cell neoplasms, termed VEXAS (vacuoles, X-linked, autoinflammatory, somatic) syndrome. Given the degree of inflammation seen, one would have expected this to be a fertile ground for CH development and propagation, however, preliminary data doesn't support this. Here in, we review the current data on CH, inflammation and VEXAS syndrome.