Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo

Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells (BMSCs) in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells upon miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in SCID/NOD mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials

The Global Atmospheric Environment for the Next Generation

Air quality, ecosystem exposure to nitrogen deposition, and climate change are intimately coupled problems: we assess changes in the global atmospheric environment between 2000 and 2030 using twenty-six state-of-the-art global atmospheric chemistry models and three different emissions scenarios. The first (CLE) scenario reflects implementation of current air quality legislation around the world, whilst the second (MFR) represents a more optimistic case in which all currently feasible technologies are applied to achieve maximum emission reductions. We contrast these scenarios with the more pessimistic IPCC SRES A2 scenario. Ensemble simulations for the year 2000 are consistent among models, and show a reasonable agreement with surface ozone, wet deposition and NO2 satellite observations. Large parts of the world are currently exposed to high ozone concentrations, and high deposition of nitrogen to ecosystems. By 2030, global surface ozone is calculated to increase globally by 1.5±1.2 ppb (CLE), and 4.3±2.2 ppb (A2), using the ensemble mean model results and associated ±1 σ standard deviations. Only the progressive MFR scenario will reduce ozone, by -2.3±1.1 ppb. Climate change is expected to modify surface ozone by -0.8±0.6 ppb, with larger decreases over sea than over land. Radiative forcing by ozone increases by 63±15, and 155±37 mWm-2 for CLE and A2, respectively, and decreases by -45±15 mWm-2 for MFR. We compute that at present 10.1 % of the global natural terrestrial ecosystems are exposed to nitrogen deposition above a critical load of 1 g N m-2 yr-1. These percentages increase by 2030 to 15.8% (CLE), 10.5% (MFR) and 25% (A2). This study shows the importance of enforcing current worldwide air quality legislation, and the major benefits of going further. Non-attainment of these air quality policy objectives, such as expressed by the SRES-A2 scenario, would further degrade the global atmospheric environment.JRC.H.2-Climate chang