Interleukin‐6 (IL‐6) is a growth factor for normal B cells and plasma cell‐derived malignancies. Here, we show that the IL‐6 signaling pathway is also active in a subset of diffuse large B‐cell lymphoma (DLBCL) patients with particularly poor prognosis. Primary DLBCL cells and DLBCL cell lines expressing IL‐6R engraft and form orthotopic lymphomas in humanized mice that ectopically produce human IL‐6, and in mice reconstituted with a human immune system. We show that a subset of DLBCL cases have evolved mechanisms that ensure constitutive activation of the IL‐6 signaling pathway, i.e., the expression of both chains of the IL‐6R, the expression of the cytokine itself, and the mutational inactivation of a negative regulator of IL‐6 signaling, SOCS1. IL‐6 signaling promotes MYC‐driven lymphomagenesis in a genetically engineered model, and treatment with the IL‐6R‐specific antibody tocilizumab reduces growth of primary DLBCL cells and of DLBCL cell lines in various therapeutic settings. The combined results uncover the IL‐6 signaling pathway as a driver and negative prognosticator in aggressive DLBCL that can be targeted with a safe and well‐tolerated biologic.

Key Points SMAD1 is silenced by hypermethylation in DLBCL cell lines and patient samples but not in peripheral blood B cells or lymph nodes. DAC treatment restores SMAD1 expression and reverses DLBCL growth in several xenotransplantation and patient-derived xenograft models.

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