Constitutive activation of Stat3 signaling confers resistance to apoptosisin human U266 myeloma cells

Interleukin 6 (IL-6) is the major survival factor for myeloma tumor cells a nd induces signaling through the STAT proteins. We report that one STAT fam ily member, Stat3 is constitutively activated in bone marrow mononuclear ce lls from patients with multiple myeloma and in the IL-6-dependent human mye loma cell line U266, Moreover, U266 cells are inherently resistant to Fas-m ediated apoptosis and express high levels of the antiapoptotic protein Bcl- x(L). Blocking IL-6 receptor signaling from Janus kinases to the Stat3 prot ein inhibits Bcl-x(L) expression and induces apoptosis, demonstrating that Stat3 signaling is essential for the survival of myeloma tumor cells. These findings provide evidence that constitutively activated Stat3 signaling co ntributes to the pathogenesis of multiple myeloma by preventing apoptosis.