| First Author | Hashwah H | Year | 2019 |
| Journal | EMBO Mol Med | Volume | 11 |
| Issue | 10 | Pages | e10576 |
| PubMed ID | 31515941 | Mgi Jnum | J:286003 |
| Mgi Id | MGI:6400075 | Doi | 10.15252/emmm.201910576 |
| Citation | Hashwah H, et al. (2019) The IL-6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B-cell lymphoma. EMBO Mol Med 11(10):e10576 |
| abstractText | 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. |
