Multiple pathways of TF deregulation in AML and MDS. (A) TFs modify the output of target genes by influencing the reaction propensities of various steps in transcription in a manner proportional to some function of TF concentration. These functions can take on a variety of shapes, depending on the number of binding sites and the higher order complexes that a given TF is involved in at a target locus. Cooperativity at a locus produces gene regulatory functions (GRF) that are sigmoidal in shape. Although not mutually exclusive phenomena, in a simplistic sense deregulation can occur either through reducing the amount of TF produced or by changing the GRF shape through changing the degree of cooperativity. In the case of gene activation, this causes different effects at the level of single cells. In the former case (left), lower TF concentrations lead to less transcription of a target at the single-cell level. In the latter case (right), the amount of TF needed to sufficiently activate a target is increased, thereby reducing the number of cells which achieve the “threshold” concentration of TF. (B) Specific etiologies whereby the master myeloid TF PU.1 is deregulated in AML and MDS. Citations found within the main text. DBD, DNA-binding domain; PEST, Pro-Glu-Ser-Thr rich domain; TAD, transactivation domain.