Model of LSC development by a malignant transcription-factor threshold illustrated on the PU.1 gene. A range of PU.1 expression between normal (100%) and haploinsufficient (50%) levels supports normal HSC differentiation into myeloid progenitors and subsequent mature granulocytes and macrophages. Graded reduction of PU.1 activity below 20% of normal meets a critical threshold level leading to poor differentiation and subsequent accumulation of an abnormal progenitor pool which is reminiscent of a preleukemic phase. Additional secondary mutations, such as c-myc overexpression because of genomic instability, complete the transformation of those cells into LSCs, which give rise to a bulk of AML blasts (leukemic phase). PU.1 function has been shown to be repressed by a number of different mechanisms in human or murine leukemia, which include down-regulation by oncogenic products as well as mutations in the PU.1 coding sequence (CDS) and deletion of the URE.