摘要/Abstract

摘要： 目的 ·应用小鼠模型，探索雷帕霉素靶蛋白（ mammalian target of rapamycin，mTOR）抑制剂雷帕霉素治疗 DNA甲基转移酶 3A（DNA methyltransferase 3A，DNMT3A）R882突变相关急性髓系白血病（ acute myeloid leukemia，AML）的效果。方法 ·将携带 DNMT3A R882突变的人 AML细胞株 OCI-AML3在体外培养，分别给予雷帕霉素或者二甲基亚砜（dimethyl sulfoxide，DMSO）处理后，由尾静脉注射给半数致死量辐照后的 NOD/SCID免疫缺陷小鼠，观察 2组小鼠的疾病进展情况。监测小鼠的血常规，通过流式细胞术检测人 CD45+细胞即 OCI-AML3细胞比例变化，记录小鼠生存时间，取小鼠骨髓、脾脏、肝脏进行病理和流式等分析。结果 ·雷帕霉素组小鼠外周血白细胞与 DMSO组相比升高趋势明显减缓，外周血 CD45+细胞比例为（ 4.44±2.58）%（移植后 1周）和（34.42±13.64）%（移植后 2周），均低于同时期 DMSO组的（ 16.71±8.96）%和（51.55±5.36）%；雷帕霉素组小鼠中位生存期 27 d，相较 DMSO组中位生存期 23 d明显延长。雷帕霉素组骨髓、脾脏和肝脏中 CD45+细胞浸润比例均小于 5%，明显低于 DMSO组脾脏（[ 51.32±27.81）%]和肝脏 [（50.03±28.74）%]中的比例；雷帕霉素组小鼠脾脏大小明显小于 DMSO组，脾脏浸润和结构破坏明显减轻。结论 ·在携带 DNMT3A R882突变的 AML免疫缺陷小鼠模型中，雷帕霉素可有效抑制 DNMT3A R882突变的 AML的进展。
关键词: 急性髓系白血病, DNA甲基转移酶 3A R882突变, 雷帕霉素, mTOR抑制剂
Abstract:
Objective · To investigate the effect of mammalian target of rapamycin (mTOR) inhibitor rapamycin on acute myeloid leukemia (AML) with DNA methyltransferase 3A (DNMT3A) R882 mutation in momodel. Methods · AML cell line OCI-AML3 cells with DNMT3A R882 mutation were cultured with the treatment of rapamycin or DMSO, and then these cells were injected into the tail vein of sublethally irradiated NOD/SCID mice, respectively. The disease progression was monitoredblood routine examination and flow cytometry analysis of CD45+, OCI-AML3 cells, in peripheral blood. Survival time was recorded. Samples bone marrow, spleen and liver were harvested for flow cytometry analysis and pathological examination. Results · The increasing trend of peripheral leukocytes in the rapamycin treated group was obviously slower than that in the DMSO treated group. The proportion of peripheral blood CD45+ cells in the rapamycin treated group was (4.44±2.58)% (1 week after transplantation) and (34.42±13.64)% (2 weeks after transplantation), which were lower than (16.71±8.96)% and (51.55±5.36)% in the DMSO treated group in the same period, respectively. The median survival time of the rapamycin treated group (27 d) was significantly longer than that of the DMSO group (23 d). The ratios of CD45+ cell infiltration in bone marrow, spleen and liver of the rapamycin treated group were all less than 5%, which were significantly lower than those [(51.32±27.81)% in spleen and (50.03±28.74)% in liver] of the DMSO treated group. Compared with the DMSO treated group, the spleen size of the mice was significantly smaller, and the spleen infiltration and structural damage were significantly alleviated in the rapamycin treated group. Conclusion · Rapamycin shows effective inhibition on the progression of AML with DNMT3A R882 mutation in NOD/SCID momodel.
Key words: acute myeloid leukemia, DNA methyltransferase 3A R882 mutation, rapamycin, mTOR inhibitor


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