NPM1 and other mutations cooperate to promote AML. (A) AML with the triple-mutated (DNMT3A/NPM1/FLT3-ITD) genotype is observed in patients and is associated with a particularly poor outcome. DNMT3A mutations are early genetic events that are responsible for the generation of a clonal hematopoiesis. NPM1 mutations are disease-defining genetic lesions that are gatekeepers for AML, whereas FLT3-ITD mutations are late events. Courtesy of Timothy Ley. (B) Hypothetical steps in the sequential development of angioimmunoblastic T-cell lymphoma (AITL) (RHOA mutation; orange) followed by NPM1-mutated AML (NPM1 mutation; pink) in a 45-year-old man. The 2 neoplasms arose from high-risk clonal hematopoiesis in the bone marrow promoted by multiple TET2 and ASXL1 mutations.⁴⁹  The TET2 Q1654* mutation (black) was present in virtually all bone marrow cells (variant allele frequency, 49.3%). The other mutations (TET2 E1089Kfs, red; TET2 Q888, gray; and ASXL1 E635Rfs, green) showing lower allele frequencies likely occurred later as subclonal events.