Clonal hematopoiesis. The diagram illustrates disease progression from clonal hematopoiesis to acute myeloid leukemia (AML). Somatic LOF mutations of TET2, DNMT3A, or ASXL1 confer a competitive advantage on HSCs and result in aberrant expansion of mutant HSC clones. This process, also known as CHIP or ARCH, can be observed in healthy individuals who may not develop clinical abnormalities for decades. The clonal diversity of HSCs contributing to hematopoiesis gradually decreases in individuals with CHIP/ARCH, concomitantly with an increase in the size of the HSC clones bearing the mutations. Secondary mutations tend to accumulate in these mutated HSCs with age, predisposing individuals with CHIP/ARCH to a higher risk of developing hematopoietic malignancies, including de novo or secondary AML. Additional factors that could contribute to cell transformation are mutations in signaling enzymes and/or epigenetic regulators, metabolic alterations, and environmental factors, including vitamin C levels, inflammation, and hypoxia (lower right).