The cooccurrence of oncogenic mutations affecting the DNMT3A and NPM1 genes, together with ITDs in FLT3, is one of the most common combinations of genetic events in AML and seems sufficient to generate the disease. The reasons for why there is a relatively high frequency of this cooccurrence and why it is associated with a worse prognosis for patients are poorly understood. Garg et al report that the 3 mutations synergize to upregulate the HLF gene in association with hypomethylation of its promoter. In turn, HLF activates a set of genes that includes HES1 (a known NOTCH target) and the cell cycle inhibitor p57 (CDKN1C). These changes are associated with enhanced self-renewal of AML cells, an increased LSC frequency, and an aberrant immunophenotype (CD56^highCD34^low) that is characteristic of the triple-mutant cells. Genetic targeting of HLF sensitized AML cells to antileukemic drugs, suggesting that targeting this pathway may represent a novel therapeutic strategy in this and potentially other AML subtypes.