A molecular informed therapy for Diffuse Intrinsic Pontine Gliomas (DIPG)

弥漫性特征的组蛋白替代水平和表观基因组图谱 在H3K27M突变的DIPG患者细胞中，我发现H3K27M与H3K27共定位 乙酰化(H3K27ac)。根据以往的生化数据，异型H3K27M- K27ac核小体与溴域蛋白共定位于活跃转录的基因， 鉴于PRC2被排除在这些区域之外，这表明PRC2没有被隔离在 H3K27M的加入。异型核小体H3K27M-K27ac共 在DIPG中用溴域蛋白定位，重要的是用BET溴域处理 DIPG异种移植小鼠模型中的抑制剂有效地抑制肿瘤生长和扩大动物 生死存亡。在我的指导阶段(K99)，我计划研究分子细节 异型核小体的体外生物化学和分子生物学研究 分析并收集关于异常乙酰化和 H3K27M在DIPG中的沉积。在向独立阶段(R00)过渡时，我 计划通过确定BET抑制剂的机制来改进BET抑制剂的治疗策略 阻力和合作因素，可导致改善和持久的儿童治疗 受DIPG影响。总而言之，我的计划是进行实验，推动我们的 对这种不治之症的了解，目标是最终拥有一种标准护理选择， 可为DIPG患者提供可靠有效的治疗方法。 先天性胶质瘤(DIP G)是一种高度侵袭性的儿童脑干肿瘤 通过迅速且近乎一致的病人死亡。一种杂合点突变 H3存在于80%以上的肿瘤中，并导致赖氨酸到蛋氨酸的转化 (H3K27M)。组蛋白突变体的表达伴随着组蛋白表达的减少 多梳抑制复合体2(PRC2)介导的H3K27三甲基化(H3K27me3) 这被认为是DIPG肿瘤发生的驱动事件。 庞蒂娜是

Diffuse characterized histone substitution levels and By profilying the epigenome of H3K27M mutant DIPG patient cells I found that H3K27M co-localizes with H3K27 acetylation (H3K27ac). In accordance with previous biochemical data, heterotypic H3K27M- K27ac nucleosomes co-localize with bromodomain proteins at actively transcribed genes, whereas PRC2 is excluded from these regions, suggesting that PRC2 is not sequestered at sites of incorporation of H3K27M. I also showed that the heterotypic nucleosomes H3K27M-K27ac co- localize with bromodomain proteins in DIPG, importantly treatment with BET bromodomain inhibitors in DIPG xenograft mouse models potently reduces tumor growth and extend animal survival. During my mentored phase (K99) I'm planning to study the molecular details of the formation of the heterotypic nucleosomes using in vitro biochemistry and molecular biology assays and gather further insights in the pathogenic mechanisms of aberrant acetylation and H3K27M deposition in DIPG. While transitioning toward the independent phase (R00) I'm planning to improve the BET inhibitors therapeutic strategy by identifying mechanisms of resistance and cooperative factors that can lead to an improved and durable therapy for children affected by DIPG. Altogether my plan is to perform experiments that push forward our knowledge of this incurable disease with the goal of finally having a standard-of-care option that can offer a reliable and efficacious treatment for DIPG patients. Intrinsic Glioma (DIP G) a highly aggressive pediatric brainstem tumor by rapid and nearly uniform patient demise. A heterozygous point mutation of H3 occurs in more than 80% of these tumors, and results in a lysine-to-methionine (H3K27M). Expression of this histone mutant is accompanied by a reduction in the of Polycomb Repressive Complex 2 (PRC2) mediated H3K27 trimethylation (H3K27me3) this is hypothesized to be a driving event of DIPG oncogenesis. Pontine is