Quinacrine靶向下调慢性髓性白血病中BCR-ABL蛋白的分子机制研究

From hydroxycarbamide to busulphan, interferon alpha, and to imatinib, the treatment of chronic myelogenous leukemia (CML) has entered into the era of imatinib. The introduction of tyrosine kinase inhibitor has greatly changed the prognosis of CML. However, tyrosine kinase inhibitor can not cure CML. Drug resistance and the existence of leukemia stem cells are two major problems needed to be addressed. Due to the critical role of BCR/ABL in the pathogenesis of CML, we proposed that BCR/ABL clearance might have the potential to cure CML. We found that quinacrine (QC)，a small molecule, could significantly down-regulation the BCR/ABL protein，including the T315 mutant protein, at clinical achievable concentration. Moreover, QC could inhibit the colony forming activity of CML CD34 positive stem/progenitor cells. Based on these findings, we will investigate the mechanism underlying QC-induced downregulation of BCR/ABL, explore the combination effect of QC and tyrosine kinase inhibitors in CML mice model. This study will provide novel insights for the treatment of CML and contribute to the cure of CML in the long run.

从羟基脲，马利兰到干扰素，再到伊马替尼（IM），慢性髓性白血病（CML）的治疗进入了IM时代。酪氨酸激酶抑制剂（TKI）的应用使CML患者的生存期得到极大的延长。但是， TKI还不能使CML患者得到根本治愈。各种耐药的出现和CML造血干细胞的存在是当前CML治疗面临的两项主要挑战。基于融合蛋白BCR/ABL是CML发病的关键性因素。我们提出一种思路，即通过清除BCR/ABL蛋白达到治愈CML的目的。我们发现，一种小分子化合物Quinacrine（QC）能够在临床可达到的药物浓度范围内显著地下调BCR/ABL的水平，包括具有T315I突变的BCR/ABL。并且QC也可以抑制CML原代CD34+细胞的克隆形成能力。本项目拟在此基础上，开展QC单独及联合TKI的体内效应研究，并探讨QC下调BCR/ABL的分子机制，从而为CML的治疗提供新的思路和治疗选择，为最终攻克CML做出贡献。

靶向BCR-ABL的酪氨酸激酶抑制剂（TKI）的使用大大改善了BCR-ABL阳性白血病的预后。然而，由于TKIs耐药和白血病干细胞的存在，需要更加有效的替代方法来治疗CML。在这项研究中，我们证明了奎纳克林（QC，一种抗疟疾的老药），可以选择性诱导BCR-ABL阳性的CML细胞和ALL细胞发生凋亡。我们发现QC显着降低了BCR-ABL蛋白水平，这个过程与靶向RNA聚合酶I来阻断BCR-ABL蛋白翻译有关。此外，QC显著抑制了CML患者原代CD34阳性白血病细胞的集落形成。在异种移植小鼠模型中，QC和伊马替尼联合使用显著抑制K562细胞肿瘤的生长，而且QC能够延长T315I突变的KBM5细胞诱导的CML小鼠的生存时间。总之，我们证明了QC通过抑制其翻译显著减少致癌BCR-ABL蛋白，这对于BCR-ABL阳性白血病患者（包括TKI耐药或复发性CML患者）具有潜在的治疗应用。