靶向组蛋白赖氨酸甲基转移酶G9A清除慢性粒细胞性白血病干细胞及机制研究

Imatinib (IM) resistance and disease recurrence are still the major problems for the patients with chronic myelogenous leukemia (CML). Leukemia stem cells (LSCs) are considered as roots of IM-resistance and CML relapse. However, the mechanisms of sustaining self-renewal of CML LSCs are still unclear. Our preliminary data revealed that G9A was highly expressed in CML LSCs. Silencing G9A in CML LSCs induced apoptosis and inhibited its ability of self-renewal. These findings impelled us to hypothesis that G9A plays a key role in maintaining survival and self-renewal of CML LSCs. This study aims to validate the hypothesis and uncover the underlying mechanism that G9A promotes self-renewal of CML LSCs; observe the elimination effect of silencing G9A in CML patient stem cells and CML mouse model. This study will validate G9A as therapeutic target to eliminate CML LSCs and provide a theoretical basis for the application of G9A inhibitor UNC0642 in the treatment of CML.

慢性粒细胞性白血病（CML）患者对伊马替尼（IM）耐药和疾病复发仍是临床上面临的一大难题。白血病干细胞（LSCs）的存在是IM耐药和疾病复发的根源，然而维持CML LSCs自我更新的机制尚不完全清楚。我们前期研究发现，组蛋白赖氨酸甲基转移酶（G9A）在CML LSCs中高表达，敲低G9A可诱导CML LSCs凋亡及抑制其自我更新的能力。基于前期结果，我们提出科学假说：G9A在维持CML LSCs的存活和自我更新中起重要作用。本课题旨在检验这一假说，进一步系统明确G9A在维持CML LSCs的存活和自我更新中发挥的关键作用；在CML病人干细胞和CML小鼠模型中验证沉默G9A表达对CML LSCs的清除作用，并揭示G9A调控CML LSCs自我更新的分子机制。本研究预期确认G9A可作为CML LSCs精准干预的新靶点，为G9A小分子抑制剂UNC0642用于治疗CML的转化医学研究提供理论依据。

慢性粒细胞性白血病（CML）患者对伊马替尼（IM）耐药和疾病复发仍是临床上面临的一大难题。白血病干细胞（LSCs）的存在是IM耐药和疾病复发的根源，然而维持CML LSCs自我更新的机制尚未明确。前期研究发现，组蛋白赖氨酸甲基转移酶G9A在CML病人白血病干细胞中高表达。使用G9A shRNA沉默G9A的表达或者其小分子抑制剂UNC0642抑制其酶活性均可以抑制CML病人白血病干细胞的存活和自我更新。靶向G9A显著延长CML白血病小鼠的生存及抑制白血病干细胞的自我更新能力，且对正常造血干细胞没有明显的毒性。机制研究表明G9A通过H3K9双甲基化沉默抑癌基因SOX6的表达，从而促进CML白血病干细胞的自我更新。本研究工作确认G9A可作为靶向清除CML白血病干细胞的有效靶点，为G9A小分子抑制剂UNC0642进一步应用于临床靶向清除CML白血病干细胞提供理论和实验依据。