| Autor: |
Abdollahzadeh B; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Cantale Aeo NM; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Giordano N; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Orlando A; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Basciani M; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Peruzzi G; Center for Life Nano- and Neuro-Science, Fondazione Istituto Italiano di Tecnologia (IIT), 00161 Rome, Italy., Grazioli P; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Screpanti I; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy., Felli MP; Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy., Campese AF; Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy. |
| Abstrakt: |
T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment. |
