DNA damage can originate in HSCs from both endogenous sources, including transcriptional, replicative, and oxidative stress, as well as from environmental or therapy related challenges [191,192,210,211], as exemplified by topoisomerase II treatment, which frequently induces balanced translocations involving the MLL (mixed lineage leukemia) gene on chromosome 11q23, associated with therapy-related AML [212,213]. This evidence concerns the gene KMT2A and acute myeloid leukemia.