Initially identified and studied in yeast as a disruptor of telomeric silencing (4, 5), DOT1L has made its scientific journey to become one of the most promising therapeutic targets to combat unfavourable gene expression in patients with MLLr leukaemia and adult acute leukaemia (AAL) (29, 129) and is now under intense investigation for its critical importance in orchestrating the immune network along with other biological processes that fall outside the scope of this review. Here, DOT1L is linked to leukemia.