我们前期研究证实白血病细胞高表达tmTNF-α可组成性活化NF-κB经典和非经典途径，导致耐药。我们用自己制备的单克隆抗体首次发现tmTNF-α本身可与TRAF1和NIK等NF-κB非经典途径的信号分子形成复合物。然而，tmTNF-α信号复合物如何激活NF-κB经典与非经典途径尚不清楚。本项目拟研究并阐明 ① tmTNF-α导致白血病细胞组成性活化NF-κB经典途与非经典途径的信号通路；② tmTNF-α激活这2条NF-κB的信号通路分别导致耐药的分子机制；③ 干扰tmTNF-α信号通路，能否提高白血病细胞对化疗的敏感性。本研究不但揭示了白血病细胞NF-κB持续性活化的新机制，阐明tmTNF-α活化NF-κB经典与非经典途径的信号转导与通路，而且还为阻断白血病细胞NF-κB组成性活化提供新的治疗靶点与线索。

Our previous study demonstrated that transmembrane TNF-α（ tmTNF-α）expressed in leukemia cells constitutively activates both canonical and noncanonical NF-κB pathways, and thus induces chemoresistance. We used a home-made monoclonal antibody against tmTNF-α to do immunoprecipitation and found that tmTNF-α recruited by itself TRAF1 and NIK containing noncanonical NF-κB signal molecules to form a signal complex. However, how does the tmTNF-α signalsome activate canonical and noncanonical NF-κB pathways is not clear. The present project aims to clarify tmTNF-α mediated signal transduction to activate canonical and noncanonical NF-κB pathways, and to explore the molecule mechanisms underlying chemoresistance of leukemia cells induced by tmTNF-α-mediated activation of canonical and noncanonical NF-κB pathways. In addition, whether targeting tmTNF-α signaling could increase sensitivity of leukemia cells to chemotherapy in vitro and in vivo will be also studied. The results of this study would not only uncover a novel mechanism by which NF-κB can be constitutively activated in leukemia cells and elucidate tmTNF-α mediated signal transduction to activate NF-κB, but also provide a novel target for and a new clue to blocking constitutive activation of NF-κB for anti-leukemia therapy.