Anti-PRDM1 (aa 734-747) polyclonal antibody

The role of retinoid-related orphan receptor gamma t (ROR gamma t) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, ROR gamma t inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with ROR gamma t-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. ROR gamma t inhibitor-treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the ROR gamma t inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1(-/-) T cells produced significantly fewer IL-10 when treated with ROR gamma t inhibitor compared with wild-type T cells. Furthermore, ROR gamma t inhibitor-treated Prdm1(-/-) Th17 cells induce more severe colitis compared with ROR gamma t inhibitor-treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which ROR gamma t drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to 50% of patients with disseminated disease, remains dismal. There is hence an urgent need for effective targeted therapy especially in the relapsed/refractory setting. Gene expression profiling studies have provided new perspectives on the molecular biology, ontogeny and classification of ENKTL and further identified dysregulated signaling pathways such as Janus associated kinase (/Signal Transducer and activation of transcription (JAK/STAT), Platelet derived growth factor (PDGF), Aurora Kinase and NF-kappa B, which are under evaluation as therapeutic targets. Copy number analyses have highlighted potential tumor suppressor genes such as PR Domain Zinc Finger Protein 1 (PRDM1) and protein tyrosine phosphatase kappa (PTPRK) while next generation sequencing studies have identified recurrently mutated genes in pro-survival and anti-apoptotic pathways. The discovery of epigenetic dysregulation and aberrant microRNA activity has broadened our understanding of the biology of ENKTL. Importantly, immunotherapy via Programmed Cell Death -1 (PD-1) and Programmed Cell Death Ligand1 (PD-L1) checkpoint signaling inhibition is emerging as an attractive therapeutic strategy in ENKTL. Herein, we present an overview of the molecular biology and genomic landscape of ENKTL with a focus on the most promising translational opportunities.