The cytotoxic treatment shapes disease evolution in t-MNs. (A) The type of cytotoxic treatment influences the genetic changes leading to t-MNs. In particular, in t-APL developing after treatment with topoisomerase II inhibitors, breakpoints are clustered within hotspot regions on chromosomes 15 and/or 17, in the PML and RARA genes, corresponding to preferential sites of topoisomerase II–mediated DNA cleavage.²⁶  (B) However, in some cases, CHIP-related mutations were detectable in t-APL, but not in dn-APL and persisted at the time of CR. (C) Elderly patients with a solid tumor, who received RT or CHT with platinum compounds or topoisomerase-I inhibitors, frequently presented CHIP and additional mutations in the DDR genes TP53, PPMD1, and CHEK2, as compared with those who received surgery, immunotherapy, or targeted therapy.²⁶  (D) Unlike adults, the majority of pediatric t-MNs were characterized by mutations arising as a consequence of cytotoxic therapy, without preexisting CHIP. Professional illustration created with BioRender.com.