The tumor suppressor and chromatin modifier cAMP response element-binding protein binding protein (CREBBP) and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), a member of the MYC oncogene family, are critically involved in brain development. Both genes are frequently mutated in the same tumor entities, including high-grade glioma and medulloblastoma. Therefore, we hypothesized that alterations in both genes cooperate to induce brain tumor formation. For further investigation, hGFAP-cre::Crebbp^Fl/Fl::lsl-MYCN mice were generated, which combine Crebbp deletion with overexpression of MYCN in neural stem cells (NSCs). Within eight months, these animals developed aggressive forebrain tumors. The first tumors were detectable in the olfactory bulbs of seven-day-old mice. This location raises the possibility that presumptive founder cells are derived from the ventricular-subventricular zone (V-SVZ). To examine the cellular biology of these tumors, single-cell RNA sequencing was performed, which revealed high intratumoral heterogeneity. Data comparison with reference CNS cell types indicated the highest similarity of tumor cells with transit-amplifying NSCs or activated NSCs of the V-SVZ. Consequently, we analyzed V-SVZ NSCs of our mouse model aiming to confirm that the tumors originate from this stem cell niche. Mutant V-SVZ NSCs showed significantly increased cell viability and proliferation as well as reduced glial and neural differentiation in vitro compared to control cells. In summary, we demonstrate the oncogenic potential of a combined loss of function of CREBBP and overexpression of MYCN in this cell population. hGFAP-cre::Crebbp^Fl/Fl::lsl-MYCN mice thus provide a valuable tool to study tumor-driving mechanisms in a key neural stem/ progenitor cell niche.

肿瘤抑制因子和染色质修饰剂 cAMP 反应元件结合蛋白结合蛋白 (CREBBP) 和 v-myc 禽类骨髓细胞瘤病毒癌基因神经母细胞瘤衍生同源物 (MYCN) 是 MYC 癌基因家族的成员，与大脑发育密切相关。这两个基因经常在相同的肿瘤实体中发生突变，包括高级别神经胶质瘤和髓母细胞瘤。因此，我们假设这两个基因的改变共同诱导脑肿瘤的形成。为了进一步研究，生成了hGFAP-cre::Crebbp ^Fl/Fl ::lsl-MYCN小鼠，其结合了Crebbp缺失和MYCN过表达在神经干细胞（NSC）中。八个月内，这些动物出现了侵袭性前脑肿瘤。第一个肿瘤是在 7 天大的小鼠的嗅球中检测到的。该位置提出了推定始祖细胞源自心室-心室下区（V-SVZ）的可能性。为了检查这些肿瘤的细胞生物学，进行了单细胞 RNA 测序，结果揭示了肿瘤内的高度异质性。与参考 CNS 细胞类型的数据比较表明肿瘤细胞与 V-SVZ 的转运放大 NSC 或激活 NSC 具有最高相似性。因此，我们分析了小鼠模型的 V-SVZ NSC，旨在确认肿瘤起源于该干细胞生态位。与对照细胞相比，突变的 V-SVZ NSC 在体外表现出显着增加的细胞活力和增殖以及减少的神经胶质和神经分化。总之，我们证明了 CREBBP 功能丧失和 CREBBP 过度表达联合的致癌潜力。该细胞群中的MYCN。hGFAP-cre::Crebbp ^Fl/Fl ::lsl-MYCN小鼠因此为研究关键神经干/祖细胞生态位中的肿瘤驱动机制提供了有价值的工具。