DIFFERENTIAL BINDING-ACTIVITY OF THE TRANSCRIPTION FACTOR LIL-STAT INIMMATURE AND DIFFERENTIATED NORMAL AND LEUKEMIC MYELOID CELLS

Cytokines and growth factors induce activation of the family of signal transducers and activators of transcription (Stats) that directly act ivate gene expression. Recently, constitutively activated Stat1, Stat3 , and Stat5 were identified in nuclear extracts of acute myeloid leuke mia (AML) patients, suggesting involvement of constitutive Stat activi ty in the events of leukemogenesis. In the present study, blasts of ni ne AML cases were investigated for the constitutive binding activity o f the recently identified transcription factor LIL-Stat (LPS- and IL-1 -inducible Stat). Band-shift assays were performed using the LPS- and IL-1-responsive element (LILRE) oligonucleotide, a gamma interferon ac tivation site-like site that is present in the human IL-1 beta promote r. Constitutive LIL-Stat binding activity was observed in three leukem ic cell lines and in seven out of nine AML cases. Transient transfecti on studies with a reporter plasmid containing three sequential LIL-Sta t binding sites showed distinct transcriptional activity of LIL-Stat o nly in those AML blasts that constitutively expressed LIL-Stat. In CD3 4+ cells LIL-Stat also constitutively bound to its consensus sequence. However, when these cells were cultured in the presence of macrophage -colony stimulating factor (M-CSF) and stem cell factor (SCF) for diff erentiation along the monocytic lineage, the LIL-Stat binding activity disappeared totally. In agreement with these findings neither mature monocytes nor granulocytes showed constitutive or inducible LIL-Stat b inding activity. We conclude that the LIL-Stat transcription factor is constitutively activated in undifferentiated and leukemic hematopoiet ic cells, but not in mature cells. This may suggest a role for this tr anscription factor in the process of differentiation. (C) 1998 by The American Society of Hematology.