Although we cannot completely exclude this possibility, some elements argue in favor of a weak impact of subclonal architecture on SLA signatures: (i) most AML at the time of diagnosis are composed of a major founding clone likely to be detected by the SLA signature [35, 48]; (ii) oncogenic mutations strongly linked to SLA are rarely found in pre-leukemic clones (except DNMT3A or TET2 mutations) but are likely a later event in leukemogenesis [49, 50]; and consequently (iii) these oncogenic events are mutually exclusive and rarely found associated in AML patients. Here, TET2 is linked to acute myeloid leukemia.