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An in vivo patient-derived model of endogenous IDH1-mutant glioma

机译:体内患者来源的内源性IDH1突变型神经胶质瘤模型

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摘要

Somatic mutations in the catalytic domain of isocitrate dehydrogenase (IDH) 1/2 and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG) appear to be among the earliest events in gliomagenesis and may contribute to malignant transformation. The lack of cell lines with endogenous mutations has been one of the major challenges in studying IDH1/2-mutant glioma and developing novel therapeutics for these tumors. Here, we describe the isolation of a glioma brain tumor stem cell line (BT142) with an endogenous R132H mutation in IDH1, aggressive tumor-initiating capacity, and 2-HG production. The neurosphere culture method was used to establish a brain tumor stem cell line from an IDH1-mutant anaplastic oligoastrocytoma sample, and an orthotopic xenograft system was developed to allow its rapid expansion. Production of 2-HG by glioma cells with endogenous IDH1 mutations was confirmed by mass spectrometry. BT142 retained an endogenous R132H IDH1 mutation in culture and possessed aggressive tumor-initiating capacity, allowing it to be readily propagated in orthotopic xenografts of nonobese diabetic/severe combined immune deficiency (NOD SCID) mice. Endogenous 2-HG production by BT142 was detectable in both cell culture medium and xenograft animal serum. BT142 is the first brain tumor cell line with an endogenous IDH1 mutation and detectable 2-HG production both in vitro and in vivo, which thus provides a unique model for studying the biology of IDH1-mutant glioma and in vivo validation of compounds targeting IDH1-mutant cells.
机译:异柠檬酸脱氢酶(IDH)1/2的催化域中的体细胞突变和oncometabolite 2-羟基谷氨酸(2-HG)的积累似乎是胶质瘤发生的最早事件之一,可能有助于恶性转化。缺乏具有内源性突变的细胞系一直是研究IDH1 / 2突变神经胶质瘤和开发针对这些肿瘤的新型疗法的主要挑战之一。在这里,我们描述了具有IDH1的内源性R132H突变,侵袭性肿瘤起始能力和2-HG产生的神经胶质瘤脑肿瘤干细胞系(BT142)的分离。使用神经球培养方法从IDH1突变型间变性少星形细胞瘤样品中建立脑肿瘤干细胞系,并开发了原位异种移植系统以使其迅速扩增。质谱证实具有内源性IDH1突变的神经胶质瘤细胞产生2-HG。 BT142在培养物中保留了内源性R132H IDH1突变,并具有激进的肿瘤起始能力,使其易于在非肥胖/严重合并免疫缺陷(NOD SCID)小鼠的原位异种移植物中繁殖。 BT142产生的内源性2-HG在细胞培养基和异种移植动物血清中均可检测到。 BT142是第一个具有内源性IDH1突变并且可在体内和体外检测到2-HG产生的脑肿瘤细胞系,因此为研究IDH1突变型神经胶质瘤的生物学以及靶向IDH1的化合物的体内验证提供了独特的模型突变细胞。

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