In contrast to the selection for activating point mutations (Y641 and A677) in the SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) domain of EZH2 described in B-cell malignancies [19,20,21], a range of loss-of-function aberrations (including in other PRC2 members) have been found in 25% of T-cell acute lymphoblastic leukaemia (ALL) cases, 3% of primary AML, 29% of secondary AML, and 15% of myeloproliferative disorders [22,23,24]. Here, SET is linked to acute myeloid leukemia.