Clonal hematopoiesis (CH) is a condition in which aged hematopoietic stem cells (HSCs) acquire somatic mutations commonly seen in leukemia despite no overt signs of hematologic disease. CH is a premalignant condition characterized by a mutation with a variant allele frequency (VAF) of at least 2% and can be detected in approximately 10% of individuals over the age of 65. The risk of acquiring a CH mutation increases by approximately 6% every 10 years (1, 2), and the overall survival rate of individuals with CH is reduced when compared with those without a CH mutation (3). Approximately 20 mutations have been classified as CH mutations, with DNMT3A, TET2, and ASXL1 being the three most common; however, other genes coding for splicing factors or signaling pathway genes, such as JAK2, are also commonly detected (2, 3).

There is increasing evidence that CH is associated with many age-related nonhematologic diseases. One plausible explanation is that the increased cytokine secretion from the immune cells that carry the CH mutations contributes to many disease conditions. Recent work has shown that CH is associated with an increased risk for acute kidney injury (4), liver fibrosis (5), diabetes and insulin resistance (6), and autoimmune conditions, such as rheumatoid arthritis (7). While CH is linked to a higher incidence of hematologic malignancies, most CH-related mortality is attributed to cardiovascular disease (CVD) (2). There have been numerous studies investigating the link between clonal hematopoiesis and cardiovascular conditions, including myocardial infarction, atherosclerosis, and ischemic stroke (8). Studies using mouse models to investigate the contribution of mutant CH cells to nonhematologic conditions were mostly conducted in the Tet2-KO mice. These studies suggest that the contribution of CH clones to atherosclerosis development could result from a myeloid bias in which mutated HSCs produce increased quantities of monocytes and macrophages that promote IL-1, IL-6, and TNF production and drive systemic and vascular inflammation (9, 10). Although JAK2 mutations are associated with a 12-fold increase in CVD risk compared with other CH mutations such as of TET2 (9), the mechanisms by which JAK2 mutations in blood cells promote plaque formation and thrombosis have not been fully investigated. The limited research conducted in Jak2-mutant mouse models has uncovered intriguing roles of immune cells, like macrophages, in CVD and has examined the connection between CVD and myeloproliferative neoplasms (MPNs) induced by Jak2 mutations (10–12).

JAK2 encodes a protein tyrosine kinase and is a critical component of the JAK/STAT pathway, which is activated by cytokines and growth factors. When a cytokine binds to its receptor, JAK2 becomes activated and, in turn, activates STAT proteins and many other pathways including PI3K/AKT and MAPK signaling. JAK2 mutations such as JAK2V617F (also known as JAK2VF) result in constitutively active JAK2 kinase and the downstream signaling pathways. JAK2 mutations are common in MPNs, such as polycythemia vera (PV) (approximately 90%–95%), essential thrombocytopenia (ET) (60%), and primary myelofibrosis (PMF) (approximately 57%) (13–16). The role of mutant JAK2 in hematopoiesis has been studied in mouse models utilizing the knockin (KI) strategy of Jak2VF, the most common JAK2 mutation in CH and myeloid neoplasms. Interestingly, most Jak2-KI mice die of thrombotic events (17), highlighting the strong proinflammatory signaling activated by hyperactive Jak2 mutations. One potential issue of using this model to study CH is the near-complete replacement of WT bone marrow cells with the Jak2VF-mutant cells, which does not recapitulate CH, as most cases harbor mutations at a very low VAF. A previous study using a chimeric transplant model reported that Jak2VF-mutant bone marrow cells promote plaque development (18), but the VAF used in that study, at 20%, was much higher than the VAF commonly observed in individuals with CH, which is typically under 10%.