Interleukin 6 (IL-6) is the major survival factor for myeloma tumor cells and induces signaling through the STAT proteins. We report that one STAT family member, Stat3, is constitutively activated in bone marrow mononuclear cells from patients with multiple myeloma and in the IL-6-dependent human myeloma cell line U266. Moreover, U266 cells are inherently resistant to Fas-mediated apoptosis and express high levels of the antiapoptotic protein Bcl-xL. Blocking IL-6 receptor signaling from Janus kinases to the Stat3 protein inhibits Bcl-xL 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 contributes to the pathogenesis of multiple myeloma by preventing apoptosis.

SUMMARY We investigated the transcriptional and epigenetic repression of miR-29 by Myc, HDAC3, and EZH2 in mantle cell lymphoma and other Myc-associated lymphomas. We demonstrate that miR-29 is repressed by Myc through a co-repressor complex with HDAC3 and EZH2. Myc contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces Myc via inhibition of the Myc targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the Myc-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, down-regulation of miR-29 targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a Myc-mediated miRNA repression mechanism, shed light on Myc lymphomagenesis mechanisms and reveals promising therapeutic targets for aggressive B-cell malignancies.

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