To functionally demonstrate oncogenic cooperation, Iacobucci and colleagues used multiplexed CRISPR/Cas9-mediated genome editing of HSPCs followed by BM reconstitution in irradiated mice.103 They established 14 genetically different leukemia mouse models in which induction or an AEL phenotype was associated with inactivation of the Bcl-6 co-repressor (Bcor) and Trp53 either alone or co-mutated with Dnmt3A, Retinoblastoma 1 (Rb1) or Nuclear factor I X (Nfix1). Here, RB1 is linked to leukemia.