三氧化二砷通过抑制XPO1/survivin信号通路诱导CLL细胞凋亡的机制研究

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.

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。

慢性淋巴细胞白血病（CLL）发病率逐年升高，高危CLL患者预后极差，常常短期内进展，目前缺乏有效的治疗方案。课题组研究发现高危CLL高表达XPO1，并且XPO1高表达与CLL不良预后因素相关；三氧化二砷（As2O3）体外可以抑制CLL细胞株以及CLL原代细胞增殖并诱导其发生凋亡；进一步证实As2O3是通过抑制XPO1/survivin通路，调控凋亡相关蛋白表达，诱导CLL细胞凋亡，抑制CLL细胞增殖。本课题组进一步在CLL荷瘤小鼠体内证实XPO1高表达在CLL发病机制中的核心作用，As2O3体内可以通过抑制XPO1/survivin通路诱导CLL凋亡，抑制CLL瘤块生长。CMML在粒细胞，单核细胞以及髓系前体细胞均可出现免疫表型的异常，尤其是在髓系前体细胞最为明显，应用流式细胞检测在髓系前体细胞发现两种或两种以上表型异常对于鉴别CMML和反应性单核细胞增多具有较高的敏感性（94.1%）和特异性（100%）。甲状腺功能减退症与乙型肝炎相关的代偿性肝硬化中的严重血小板减少症有关；泼尼松加左甲状腺素片治疗可能为这些患者提供了一种新方法。ITP患者骨髓交感神经受损以及nestin+的MSCs凋亡增加可能导致ITP患者骨髓CXCL12减少，CXCL12/CXCR4异常，从而导致MK分布异常，血小板生成减少。本课题的发现为高危CLL的发病机制提供了新的理论基础，为CLL的治疗提供了潜在的新思路，XPO1有望成为治疗CLL潜在的新靶点，为As2O3治疗高危CLL提供一个新方法。课题进一步深入并拓展到老年患者其他血液肿瘤的诊治如CMML、淋巴瘤等。