STAT signaling in the pathogenesis and treatment of leukemias

Leukemias continue to cause significant mortality in adults and children, a nd the use of standard cytotoxic chemotherapy has reached a therapeutic pla teau, Thus, there is great interest in treatments directed against inapprop riately activated cell signaling pathways which stimulate the uncontrolled growth of neoplastic cells. Increasing evidence suggests that the STAT sign aling cascade may be one target of these therapies. Signal transducer and a ctivator of transcription (STAT) proteins are critical in mediating the res ponse of hematopoietic cells to a diverse spectrum of cytokines. Constituti ve STAT activation is present in many malignancies and has been especially well characterized in acute and chronic leukemias. While STAT activation is a common characteristic of leukemias, the specific pattern of activated ST ATs and the manner by which STAT activation occurs vary with each disease. STAT tyrosine phosphorylation can occur through inappropriate Jak activatio n or by direct activation of an oncoprotein such as Bcr/Abl, and STAT serin e phosphorylation may play an important role in leukemias as well. Thus, th e STAT signaling pathway is an attractive target for therapeutic interventi on, and strategies designed to inhibit STAT activation and STAT mediated ge ne transcription may play an important role in the next generation of anti- leukemia therapies.