ABL1/p73信号通路是MM细胞DNA损伤诱导细胞凋亡的重要途径。前期研究发现p73蛋白异构体在MM细胞中表达失衡，TAp73表达降低，DNp73表达升高并具有临床预后意义。并且证实敲减DNp73表达可抑制MM细胞增殖，增加其对DNA损伤药物的敏感性。ChIP-seq及表达谱芯片结果显示转录因子NF-κB和选择性剪切因子SLU7参与DNp73基因表达调控。据此我们提出TAp73/DNp73表达失衡是MM细胞抵抗DNA损伤诱导细胞凋亡的重要原因，高表达DNp73竞争性结合ABL1激酶，抑制细胞凋亡，促进MM细胞增殖与耐药，导致患者生存期缩短的科学假设。本研究拟从基因、蛋白水平，体外及体内实验等多层次探讨TAp73/DNp73表达失衡在MM细胞DNA损伤细胞凋亡中的分子机制。并结合RNA-seq等高通量检测方法，探明DNp73作用关键信号通路及调控分子，为寻找新的治疗靶点提供理论及实验基础。

Aberrant DNA damage response pathways are implicated in the development and drug-resistance induction of multiple myeloma. Our previous study showed that even in the presence of great DNA insult, myeloma cells consistently evade apoptosis even under basal conditions. The ABL1/p73 is an alternative pathway which triggers apoptosis following DNA damage in myeloma cells. Strikingly, even in the presence of elevated ABL1 expression apoptosis was undetectable in the myeloma cells tests. As the down-stream of ABL1, the expression balance of p73 isoform TAp73 and DNp73 was broken. TAp73 was down-regulated and DNp73 was up-regulated significantly in myeloma cells. Kaplan-Meier analyses showed that myeloma patients with higher expression of DNp73 had a significantly inferior survival. shRNA knock-down DNp73 expression suppressed myeloma cells proliferation and promoted the sensitivity of myeloma cells to DNA damage reagent doxorubicin induced apoptosis. ChIP-seq and gene expression profiles (GEP) of tumor cells in myeloma patients suggested that transcription factor NF-κB and alternative splicing factor SLU7 contributed to DNp73 over-expression in myeloma cells. It is our hypothesis that down-regulation of TAp73 and up-regulation of DNp73 promotes myeloma cells proliferation and against DNA damage response induced apoptosis. Activation of NF-κB transcription factor and higher level of splicing factor SLU7 increased DNp73 up-regulation in myeloma cells. DNp73 competitive combined with ABL1 kinase and suppressed myeloma cells apoptosis induced by DNA damage response. This mechanism also contributed to drug-resistance of myeloma cells. Therefore, this project will investigate TAp73 and DNp73 functions of cell proliferation and drug resistance in multiple myeloma. Combined with RIP, ChIP-seq and TAP/MS high-throughput assay, Co-IP experiments, as well as 5TGM1 mouse myeloma model, the DNp73 key signaling pathways and the role of regulatory molecules will be clarified. The results will provide theoretical and experimental foundation for the search for new therapeutic targets in multiple myeloma.