Age-Associated Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease

Acquired, inactivating mutations in Tet methylcytosine dioxygenase 2 () are detected in peripheral blood cells of a remarkable 5%-10% of adults greater than 65 years of age. They impart a hematopoietic stem cell advantage and resultant clonal hematopoiesis of indeterminate potential (CHIP) with skewed myelomonocytic differentiation. CHIP is associated with an overall increased risk of transformation to a hematological malignancy, especially myeloproliferative and myelodysplastic neoplasms (MPN, MDS) and acute myeloid leukemia (AML), of approximately 0.5% to 1% per year. However, it is becoming increasingly possible to identify individuals at greatest risk, based on CHIP mutational characteristics. CHIP, and particularly -mutant CHIP, is also a novel, significant risk factor for cardiovascular diseases, related in part to hyper-inflammatory, progeny macrophages carrying mutations. Therefore, somatic mutations contribute to myeloid expansion and innate immune dysregulation with age and contribute to prevalent diseases in the developed world-cancer and cardiovascular disease. Herein, we describe the impact of detecting mutations in the clinical setting. We also present the rationale and promise for targeting -mutant and other CHIP clones, and their inflammatory environment, as potential means of lessening risk of myeloid cancer development and dampening CHIP-comorbid inflammatory diseases.