NR2F2通过调控NF-κB通路参与PTPN21介导的急性淋巴细胞白血病耐药的机制研究

The chemo-resistance of acute lymphoblastic leukemia (ALL) is one of the main obstacles to overcome in the process of treatment. It also plays an important role in poor prognosis and low survival rate of ALL patients. Exploring the mechanisms of chemo-resistance in ALL can provide evidence for target therapy in refractory and recurrent leukemia, which has important values of clinical application. Our previous research found that PTPN21 was abnormally highly-expressed in ALL patients. Furthermore, the high expression of PTPN21 may play an important role in chemo-resistance of ALL. Subsequent results of digital gene expression profiling revealed that NR2F2 was down-regulated in cells over-expressed PTPN21. Based on previous reports, we speculated that PTPN21 may regulate the chemo-resistance of ALL through down-regulation of NR2F2, which may activate NF-kappa B pathway. This project aims to explore the key role of PTPN21 involved in chemo-resistance, clarify specific mechanisms of NR2F2/NF-kappa B signaling pathway regulated by PTPN21 and provide new methods for the treatment of refractory and recurrent ALL.

急性淋巴细胞白血病对化疗药物的耐药是治疗过程中需要克服的主要障碍之一，也是导致患者预后差、生存率低的一个重要原因。深入探索急淋细胞耐药的机制能够为靶向治疗难治复发的白血病提供证据，具有重要的临床价值。我们的前期研究结果发现PTPN21基因在急淋患者中异常高表达，而且PTPN21的高表达可能在急淋的耐药中发挥重要作用，数字基因表达谱分析发现NR2F2在过表达PTPN21的急淋细胞中表达下调，结合已有文献报道，我们推测PTPN21可能通过下调NR2F2从而激活NF-κB通路参与调控急性淋巴细胞白血病的耐药。本项目旨在探索PTPN21参与耐药的关键机制，阐明PTPN21调控NR2F2/NF-κB信号通路的具体机制，为治疗难治复发的急淋提供新思路。

急性淋巴细胞白血病对化疗药物的耐药是治疗过程中需要克服的主要障碍之一，也是导致患者预后差、生存率低的一个重要原因。深入探索急淋细胞耐药的机制能够为靶向治疗难治复发的白血病提供证据，具有重要的临床价值。我们的前期研究结果发现PTPN21基因在急淋患者中异常高表达，通过在急淋细胞株Jurkat和NALM-6中过表达PTPN21，我们证实PTPN21的高表达抑制长春新碱诱导的急淋细胞凋亡，这说明PTPN21可能参与调控急淋的耐药。高通量转录组测序分析发现GADD45A在长春新碱诱导凋亡的过表达PTPN21细胞中表达下调，同时下游JNK通路磷酸化受抑制，恢复GADD45A表达可逆转PTPN21抑制的长春新碱诱导急淋细胞凋亡。本研究结果表明PTPN21可能通过下调GADD45A从而抑制JNK通路参与调控急性淋巴细胞白血病的耐药。本项目通过探索PTPN21参与耐药的关键机制，发现GADD45A/JNK通路调控耐药机制，而PTPN21作为磷酸酶，可能成为治疗难治复发的急性淋巴细胞白血病的新靶点。