Analyses of neonatal blood spots, the blood collected by heel prick test, have suggested that KMT2A-AFF1 translocations arise in utero and rapidly lead to the development of overt ALL, often at or shortly after birth.10–12 This argues in favor of the existence of preleukemic clones that do not need cooperating mutations to develop a malignant disease.10,13 In the last 20 years, several groups have investigated the role of cooperating mutations in the development, maintenance, and relapse of KMT2A-rearranged leukemia. This evidence concerns the gene AFF1 and leukemia.