Although PU.1 mutations are uncommon in human AML,25, 26, 27, 47, 56 upstream mechanisms causing reduced PU.1 expression and function are well described for the fusion genes RUNX1-ETO11 and PML-RARA,28, 57 as well as by FLT3-ITD mutations.58, 59 Analysis of primary AML samples using the set of 96 PU.1 target genes, clustered the majority of RUNX1-ETO and PML-RARA samples together in a group characterised by low PU.1 expression. This evidence concerns the gene SPI1 and acute myeloid leukemia.