规范治疗后高危慢性淋巴细胞白血病（CLL）缓解率低下是CLL治疗亟待解决的重要临床难题，进一步阐明其发病机制和提高疗效具有重要理论及临床意义。申请者前期研究发现，XPO1基因在CLL患者高表达且与预后因素密切关联，三氧化二砷（As2O3）抑制人高危CLL细胞增殖和诱导凋亡，下调XPO1及survivin表达。这一发现目前国内外均未见报道，强烈提示高危CLL表达XPO1可能是一种新的CLL相关发病机制，在高危CLL中起关键的调控作用。因此，本课题拟进一步扩大样本，深入研究As2O3对CLL细胞生长及凋亡的影响，体内外实验证实XPO1高表达在CLL发病机制中的核心作用，进一步证实XPO1对survivin信号通路及凋亡相关蛋白调控作用，探索As2O3可能通过抑制XPO1/survivin通路诱导CLL凋亡的机制。XPO1有望成为治疗CLL潜在的新靶点，为As2O3治疗高危CLL提供一个新思路。

The low response rate of standard treatments in high-risk of chronic lymphocytic leukemia (CLL) is an important clinical problem to be solved. It is of great theoretical and clinical significance to further clarify the pathogenesis and improve the therapeutic effect. In preliminary studies, the applicant found that XPO1 expression levels of CLL patients were higher than those of controls, and the higher levels of XPO1 were related with the poor prognostic factors in patients with CLL. Arsenic trioxide (As2O3) could inhibit proliferation and induce apoptosis of human CLL cells in vitro. It has been found that the effect was accomplished with down-regulation of XPO1 and survivin. These findings have not been reported at home and abroad. It is suggested strongly that XPO1 may be a new type of pathogenesis in CLL and play a key role in the high-risk CLL. Therefore, we plan to further investigate the effect of As2O3 on the growth and apoptosis of CLL cells. We plan to further confirm that high-level expression of XPO1 is of a central role in the pathogenesis of CLL in vitro and in vivo. We want to further explore the effect of XPO1 in regulation of survivin signaling pathway and in regulation of protein related to apoptosis. We also want to identify whether the mechanism of inhibition effect of As2O3 in CLL may be relevant to induce apoptosis by inhibiting XPO1/survivin signaling pathway. XPO1 is expected to become a potential new target for the treatment of CLL, and offers a potential new therapeutic strategy for using As2O3 in treatment of high risk CLL patients.