The ETS transcription factor PU.1 (OF; PU.1; SFPI1; SPI-1; SPI-A; SPI) is encoded by the gene Sfpi1, which are located on human chr 11 and in the mouse on chr 2. PU.1 was first identified in mice by its erythroleukemia promoting activity as the result of spleen focus forming virus proviral integration into and subsequent activation of the spi-1 gene^[1][2]. The ETS subfamily members, Ets, Elf, Erg, Tel, PEA, and other members are often transcriptional activators and expressed in many cell types. In contrast, PU.1 is predominantly expressed in various hematopoietic lineages and, interestingly, in the germinal compartment of embryonic testis, at least from E12.5 onward. Two PU.1 protein isoforms are produced from the spi-1 gene, a 271 aa and a 270 aa (~31 kDa) protein, which are able to bind as monomers via the C-terminal 84 aa ETS domain, a hallmark of ETS factors, to target genes containing the purine rich consensus sequence 5'-AAAG(A/C/G)GGAAG-3'. PU.1 activates transcription via its N-terminal glutamine-rich and acidic domains. The PU.1 ETS domain binds the 5'-GGAA-3' core sequence by a loop-helix-loop motif ^[3]. Since many myeloid genes are TATA-less, PU.1 functions as a basal transcription factor, and in many case, regulates gene expression in coordination with others transcription factors and cofactors. A large majority of myeloid growth and differentiation genes are regulated by PU.1, such as the macrophage colony-stimulating factor receptor (CSF R), granulocyte-CSF R, and granulocyte-macrophage-CSF R ^[4]. Moreover, PU.1 functions with many critical transcription factors needed for cellular functions, e.g., p53 ^[5], C/EBP alpha/beta/epsilon, gp91phox^[6], GATA-1/-2^[7], c-Jun, NONO, and MBP-P2. PU.1 is predominantly found in early hematopoietic progenitors, myeloid and early T cell lineage, monocytes/macrophages, granulocytes, and B lymphocytes. PU.1 may downregulate its target genes through epigenetic modification ^[8]. Loss of PU.1 expression and/or activity in hematopoietic cells results in blockage of myeloid differentiation at or just after the common myeloid progenitor stage. In the mouse, low levels of PU.1 result in abnormal differentiation and proliferation, eventually resulting in myeloid leukemia. In humans PU.1 expression is severely impaired in patients with chronic myeloid leukemia at diagnosis. However, the PU.1 suppression is abrogated after interferon-alpha or imatinib treatment. These effects are not found in patients with other myeloproliferative diseases such as polycythemia vera or essential thrombocythemia^[9].