HSPB8在地西他滨以及地西他滨与伊马替尼协同抗CML中的作用研究

Decitabine is a demethylating agent and has become a treatment for chronic myelogenous leukemia (CML). The critical gene through which decitabine exerts anti-leukemia effect is still unknown. Combinatorial delivery of decitabine and imatinib synergize to confer superior therapeutic effect, but the underlying mechanism remains elusive. While carrying out the last National Natural Science Foundation of China, we found that promoter DNA of HSPB8 was methylated in hematopoietic tumor cell lines, primary patients and normal volunteer samples. HSPB8 expression could be restored after demethylation treatment with decitabine. Overexpression of HSPB8 exerted anti-leukemia effect, and enhanced imatinib mesylate-induced apoptosis in CML cell line. These data has been published in SCI journal. Based on these findings, we intend to investigate whether HSPB8 plays an important role in the anti-CML effect mediated by decitabine; further verify the ability of HSPB8 in enhancing the sensitivity of CML cell line to imatinib; elucidate the function of HSPB8 in the synergistic effect of decitabine and imatinib in CML therapy. The accomplishment of this project may lay a foundation for finding the molecular marker for demethylation therapies, provide clues for elucidating the mechanism underlying the synergistic effect of decitabine and imatinib, and provide theoretical basis for choosing more efficacious therapy for CML.

去甲基化药物地西他滨可用于慢性粒细胞白血病（CML）的治疗，但介导其抗CML作用的重要基因尚不清楚。地西他滨与伊马替尼具有协同抗CML作用，作用机制亦未阐明。我们在进行上一个国家自然基金课题时首次发现白血病患者中小分子热休克蛋白HSPB8启动子处于高度甲基化状态，HSPB8可被地西他滨诱导表达，过表达HSPB8具有抗CML作用，并可增强CML细胞对伊马替尼的敏感性，已发表SCI收录论文。本课题在前期发现的基础上拟：1. 探讨HSPB8是否在地西他滨抗CML中发挥重要作用；2. 搞清HSPB8在地西他滨与伊马替尼协同抗白血病效果中所起的作用和机制。对上述问题的探索，将可能为找到地西他滨去甲基化治疗CML的分子标志物奠定基础，为阐明地西他滨和伊马替尼协同抗白血病作用机制提供线索，为临床应用更有效针对CML的治疗方案提供理论依据。

去甲基化药物地西他滨可用于慢性粒细胞白血病（CML）的治疗，但介导其抗CML作用的重要基因尚不清楚。地西他滨与伊马替尼具有协同抗CML作用，作用机制亦未阐明。HSPB8（又称HSP22）参与调节细胞的增殖、凋亡，但其在造血系统恶性肿瘤中的作用研究尚少。本项目研究发现，HSPB8在CML患者中低表达，其启动子区存在高甲基化，地西他滨处理可使HSPB8表达恢复，并发挥肿瘤抑制作用。CML病人标本HSPB8甲基化水平与HSPB8表达水平呈负相关；CML细胞系和病人标本中HSPB8甲基化水平与地西他滨诱导的HSPB8表达及白血病细胞凋亡呈负相关；体外实验证实地西他滨介导的白血病细胞生长抑制部分依赖于HSPB8的诱导表达； 体内实验证实地西他滨介导的白血病细胞生长抑制与HSPB8的诱导表达的有密切关系；异位表达HSPB8能增加CML细胞对伊马替尼的敏感性。上述结果表明，HSPB8在地西他滨抗CML中发挥重要作用，HSPB8增强CML细胞对伊马替尼敏感性，与地西他滨和伊马替尼的协同作用相关。上述研究为临床应用更有效针对CML的治疗方案提供理论依据。