miR-30a/BCL11A调控MDM2-P53通路介导慢性髓系白血病伊马替尼耐药机制的研究

Imatinib resistance is the leading cause of treatment failure in chronic myelogenous leukemia (CML). Currently, there is no effective strategy in overcoming imatinib-induced drug resistance. Further exploration of the molecular mechanism of imatinib resistance, as well as pursuing aggressively for the new therapeutic target, might contribute to the improvement of poor prognosis in CML. Here, we reported that imatinib-resistant cells have a lower expression of miR-30a either in primary patient cells or cell lines, while its target gene BCL11A expresses higher. What’s more, up-regulation or down-regulation of miR-30a and BCL11A significantly revered the sensitivity of imatinib-resistant cells to imatinib, suggesting that miR-30a and its target gene BCL11A might take participate in the imatinib resistance in CML. Mechanically, the reversible effect of imatinib’s sensitivity was closely associated with the activation of downstream MDM2-p53 pathway. However, how miR-30a regulates BCL11A and how BCL11A regulates MDM2/P53 pathway towards imatinib resistance in CML still unclear. In this study, we will prove that miR-30a and its target gene BCL11A takes participate in the imatinib resistance of CML through the activation of MDM2-P53 pathway by molecular, cell, animal and clinic level. Meanwhile, our investigation contributes to further exploration of the molecular mechanism of imatinib resistance, which offered new strategies for the treatment of imatinib-resistant CML patients.

耐药是伊马替尼治疗慢性髓系白血病（CML）失败的主要原因，目前尚无克服伊马替尼耐药的有效策略，深入了解CML伊马替尼耐药的新机制，寻找新的治疗靶点，无疑将有助于提高CML的预后。我们研究发现miR-30a在伊马替尼耐药的原代细胞及细胞株中表达减低，而BCL11A却异常高表达，调控miR-30a和BCL11A水平能显著影响CML伊马替尼耐药细胞的敏感性，提示miR-30a和BCL11A可能参与CML伊马替尼耐药，进一步研究发现BCL11A可能是通过影响MDM2-P53通路来调控CML伊马替尼耐药。但miR-30a如何调控BCL11A及BCL11A是如何影响MDM2-P53通路导致CML伊马替尼耐药尚不清楚。本研究拟在前期工作基础上进一步从分子、细胞、动物和临床水平阐明miR-30a/BCL11A通过调控MDM2-P53通路参与伊马替尼耐药的新机制，为CML伊马替尼耐药治疗提供新靶点和新策略。

耐药是伊马替尼治疗慢性髓系白血病（CML）失败的主要原因，目前尚无克服伊马替尼耐药的有效策略，深入了解CML伊马替尼耐药的新机制，寻找新的治疗靶点，无疑将有助于提高CML的预后。辛伐他汀是一种著名的HMG-CoA还原酶抑制剂，在心血管领域表现出巨大的临床效益，因其对多种肿瘤的效抗肿瘤作用而受到越来越多的关注。在本研究中，我们验证了辛伐他汀单药治疗可有效降低伊马替尼敏感和伊马替尼耐药CML细胞的细胞活力，后者比前者更脆弱。重要的是，我们报道了辛伐他汀作为一种致敏剂在体外和体内模型中杀伤伊马替尼耐药的CML细胞。在机制上，辛伐他汀和伊马替尼的协同作用与下调PI3K/Akt信号通路的活性有关，PI3K/Akt信号通路是BCR-ABL激酶的经典下游促生存级联反应。此外，这种药物联合的协同作用通过减弱典型的Wnt/β-Catenin信号和富集H3K27三甲基化来降低Myc的表达。综上所述，这些发现提供了辛伐他汀和伊马替尼联合治疗伊马替尼耐药CML的临床前结果，为进一步开展伊马替尼耐药CML患者的临床研究提供了依据。