In KMT2A-rearranged acute leukemias, the KMT2A fusion protein is considered to be the main oncogenic driver and loss of DOT1L was shown to specifically decrease KMT2A fusion-driven transcriptional programs, including the expression of HOXA9. [7] Therefore, we asked whether acquired resistance to DOT1L inhibition was accompanied by an altered dependency on DOT1L, KMT2A::AFF1 and/or HOXA9. Here, HOXA9 is linked to acute leukemia.