Clonal evolution of myeloid malignancies

Through intensive efforts of genome sequencing of myeloid malignancies, a comprehensive registry of driver mutations has been revealed, virtually providing us with a complete spectrum of driver mutations in these diseases. Importantly, there have been significant correlations between driver mutations, which suggests that some combinations of genetic events confer strong selective advantage on mutated stem cells. Next-generation sequencing technology have also revealed that clonal hematopoiesis is a common, age-related process in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. Furthermore, novel germline mutations were identified, indicating that mutated stem cells appear long before myelodysplastic syndrome (MDS) presentation. Such founding mutations are thought to be acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis, ultimately giving rise to MDS and subsequent transformation to acute myeloid leukemia (AML) in many patients.