Clonal Evolution During Stress Hematopoiesis

Hematopoietic stem and progenitor cells (HSPCs) acquire somatic mutations with age resulting in a heterogeneous cell population, with each HSPC possessing its own unique set of private mutations. HSPCs that acquire somatic mutations that confer a competitive fitness advantage relative to their normal counterparts may clonally expand. Indeed, several groups have documented the presence of clonal hematopoiesis in healthy individuals. Although originally thought to be limited to older individuals, a recent study using an ultra-sensitive sequencing technique showed that expanded hematopoietic clones are detectable in the majority of healthy 50-60-year-old individuals. With some notable exceptions, the same genes that are commonly mutated in clonal hematopoiesis also are somatically mutated in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, only a small fraction of individuals with clonal hematopoiesis subsequently develop a myeloid malignancy and the size of the mutant clone in clonal hematopoiesis can remain stable for years without disease progression. These observations raise several questions that will be addressed in this presentation. What drives expansion of hematopoietic clones? What role do external hematopoietic stressors, such as exposure to chemotherapy, play in the development of clonal hematopoiesis? Why do so few people with clonal hematopoiesis develop a myeloid malignancy, and are there certain mutations that confer a higher risk of transformation?