Given the dependence of the dual H3K36me3-H3K79me2 signature across MLL-target genes on SETD2 and the strong requirement of MLL-leukemia for the H3K79 methyltransferase DOT1L21, we reasoned that SETD2 loss might cooperate with pharmacologic inhibition of DOT1L. Here, DOT1L is linked to leukemia.