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首页> 美国卫生研究院文献>Neuro-Oncology >TMOD-04. DETERMINING THE NEUROANATOMICAL AND CELLULAR ORIGIN OF BRAFV600E MUTANT CDKN2A DELETED GLIOMAS AND MECHANISMS OF TRANSFORMATION BY BRAFV600E EXPRESSION IN TRANSGENIC MICE
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TMOD-04. DETERMINING THE NEUROANATOMICAL AND CELLULAR ORIGIN OF BRAFV600E MUTANT CDKN2A DELETED GLIOMAS AND MECHANISMS OF TRANSFORMATION BY BRAFV600E EXPRESSION IN TRANSGENIC MICE

机译：TMOD-04。确定BRAFV600E突变型CDKN2A缺失胶质瘤的神经和细胞起源以及通过BRAFV600E表达在转基因小鼠中转化的机制

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Expression of the constitutively active BRAF -mutant kinase occurs in pediatric and predominantly young adult high-grade glioma patients (Cancer Res. 2010, 70:512; Acta Neuropathol. 2011, 121:397). BRAF expression frequently coincides with CDKN2A deletion and marks a subgroup of predominantly hemispheric tumors with epigenetic similarities to pleomorphic xanthastrocytoma (PXA) and histologic features of grade IV astrocytoma (Cancer Cell 2018, 33:829). The origin of BRAF mutant astrocytoma is under investigation. Here, we are using transgenic mice to assess neuroanatomical aspects and effects on differentiation of BRAF expression. In previous studies, expression of BRAF in astroglial cells and neural stem cells of the developing brain led to hyperplasia in transgenic mice. To circumvent the early postnatal lethality associated with BRAF expression during development, my lab injected adenovirus expressing Cre recombinase into the corpus callosum of BRAFCA Ink4a/Arf floxed young adult mice. In these mice, Cre expression induces BRAF expression and deletion of Ink4a/Arf, the mouse locus homologous to human CDKN2A. This approach showed that BRAF expression and CDKN2A (Ink4a/Arf) deficient corpus callosum cells form high-grade astrocytoma-like tumors in young adult mice (Proc Natl Acad Sci. 2012, 109:8710). To further investigate the neuroanatomical aspects of tumor formation we directed cre expression to distinct neuroanatomical areas, including the cortex, of the young adult mouse brain. Histo-pathologic and survival analyses showed that each injected area was susceptible to tumor formation albeit with different latency. Induction of BRAF expression in Ink4a/Arf-deleted neurospheres decreased the capacity for neuronal and glial differentiation and led to expansion of oligodendrocyte progenitor-like cells (OPC). Ongoing studies investigate directly the extent to which BRAF expression in Ink4a/Arf-deleted OPC in transgenic mice cause tumor formation. Results from cell of origin studies are expected to inform which mouse model most faithfully recapitulates the human diseases.
机译：组成型活性BRAF突变激酶的表达发生在儿科且主要是年轻的成人高级别神经胶质瘤患者中（Cancer Res。2010，70：512; Acta Neuropathol。2011，121：397）。 BRAF表达经常与CDKN2A缺失相吻合，并标志着一个主要的半球肿瘤亚组，其与多形性黄体星形细胞瘤（PXA）具有表观遗传相似性，并具有IV级星形细胞瘤的组织学特征（Cancer Cell 2018，33：829）。 BRAF突变型星形细胞瘤的起源正在研究中。在这里，我们正在使用转基因小鼠来评估神经解剖学方面以及对BRAF表达分化的影响。在先前的研究中，BRAF在发育中脑的星形胶质细胞和神经干细胞中的表达导致转基因小鼠的增生。为了避免发育过程中与BRAF表达相关的出生后早期致死性，我的实验室将表达Cre重组酶的腺病毒注射到BRAFCA Ink4a / Arf融合的成年幼鼠的call体中。在这些小鼠中，Cre表达诱导BRAF表达和Ink4a / Arf（与人CDKN2A同源的小鼠基因座）的缺失。该方法表明，BRAF表达和CDKN2A（Ink4a / Arf）缺陷体细胞在年轻成年小鼠中形成高度星形细胞瘤样肿瘤（Proc Natl Acad Sci。2012，109：8710）。为了进一步研究肿瘤形成的神经解剖学方面，我们将cre表达定向到了不同的神经解剖学区域，包括年轻成年小鼠大脑的皮质。组织病理学和生存分析表明，尽管有不同的潜伏期，但每个注射区域都易于形成肿瘤。在Ink4a / Arf缺失的神经球中诱导BRAF表达降低神经元和神经胶质分化的能力，并导致少突胶质祖细胞样细胞（OPC）的扩增。正在进行的研究直接调查了转基因小鼠中Ink4a / Arf缺失的OPC中BRAF表达的程度导致肿瘤形成。起源细胞研究的结果有望告知哪种小鼠模型最忠实地概括了人类疾病。

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