By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. Here, MYB is linked to acute myeloid leukemia.