CONSTITUTIVE ACTIVATION OF A SLOWLY MIGRATING ISOFORM OF STAT3 IN MYCOSIS-FUNGOIDES - TYRPHOSTIN AG490 INHIBITS STAT3 ACTIVATION AND GROWTHOF MYCOSIS-FUNGOIDES TUMOR-CELL LINES

Mycosis fungoides (MF) is a low-grade cutaneous T cell lymphoma of unk nown etiology. In this report, the Jak/Stat (Janus kinase/signal trans ducer and activator of transcription) signaling pathway was investigat ed in tumor cell lines established from skin biopsy specimens from a p atient with MF. Jaks link cytokine receptors to Stats, and abnormal Ja k/Stat signaling has been observed in some hemopoietic cancers. In MF tumor cells, a slowly migrating isoform of Stat3, Stat3(sm), was found to be constitutively activated, i.e., (i) Stat3(sm) was constitutivel y phosphorylated on tyrosine residues, and tyrosine phosphorylation wa s not enhanced by growth factor stimulation; (ii) band shift assays an d immunoprecipitations of DNA/Stat complexes showed consititutive DNA- binding properties of Stat3(sm); and (iii) Stat3(sm) was constitutivel y associated with Jak3. The abnormal activation of Stat3(sm) was highl y specific. Thus, neither the fast migrating isoform of Stat3 (Stat3(f m)) nor other Stats (Stat1, Stat2, and Stat4 through Stat6) were const itutively activated. The Jak kinase inhibitor, tyrphostin AG490, block ed the constitutive activation of Stat3(sm) and inhibited spontaneous as well as interleukin 2-induced growth of MF tumor cells. In conclusi on, we have provided evidence for an abnormal Jak/Stat signaling and g rowth regulation in tumor cells obtained from affected skin of an MF p atient.