Within the development of BFM-AIEOP protocols, high-risk (HR) and very high-risk (VHR) leukemia genetics were first defined by t(9;22)/BCR-ABL fusion (Ph+ ALL), and KMT2A-AFF1 [t(4;11), MLL-AF4], followed later on by a low hypodiploid chromosome number, the gene fusion TCF3-HLF [t(17;19)], and last the combination of IKZF1 deletion with any of CDKN2A, CDKN2B, PAX5, and/or PAR1 (CRLF2) in the absence of ERG deletions (IKZF1plus). The gene discussed is KMT2A; the disease is leukemia.