By taking this approach in cell lines modelling the main leukaemia classes, that is MLL-rearrangements, t(8;21) translocations, and complex karyotypes, we have shown that while MLL-driven AML requires MYB to enforce self-renewal and a myeloid differentiation barrier, complex karyotype leukaemia shows a reduced dependency on MYB expression. Here, KMT2A is linked to acute myeloid leukemia.