High H3K79me is maintained in the lymphomas these mice develop, and a reduction in DOT1L activity by heterozygous deletion of Dot1L reduces tumor burden, an effect that was not observed upon homozygous deletion of Dot1L. Furthermore, DOT1L inhibitors induce apoptosis in Hdac1‐deficient but not Hdac1‐proficient thymic lymphoma cell lines, suggesting a DOT1L‐dose dependence. Here, HDAC1 is linked to lymphoma.