Identifying the Second Hit in MYC-driven Medulloblastoma; a Role for Gfi Proteins

描述（申请人提供）：髓母细胞瘤（Medulloblastoma， MB）是儿童最常见的恶性脑肿瘤。最近的研究将MB分为4个分子亚群：WNT， SHH， Group 3和Group 4。虽然WNT和SHH肿瘤具有相对良好的预后，但第3组肿瘤（以MYC癌基因过表达为特征）更具侵袭性，几乎总是致命的。我们实验室最近用编码Myc和显性阴性p53肿瘤抑制因子（DNp53）的病毒感染神经干细胞（NSCs），然后将这些细胞移植回免疫缺陷小鼠的小脑，建立了第一个3mb组小鼠模型。尽管最终的肿瘤与人类3mb组相似，但该模型并不能精确地概括人类疾病的遗传学，因为大多数人类3组肿瘤没有表现出p53的突变或缺失。因此，我们研究的一个主要目标是确定与MYC合作并与人类MB相关的第二点。最近的全基因组测序分析已经确定了两个染色体位点，它们是3mb组重排的热点。这些位点的重排激活锌指转录抑制因子Gfi1和Gfi1b。重要的是，我们的初步数据显示Gfi1和Gfi1b都可以与Myc合作，驱动小鼠MB的形成。基于这些事件在人类3mb组中惊人的普遍性，以及之前关于Gfi1在白血病中与Myc合作的报道，我们假设Gfi蛋白是3mb组肿瘤发生的关键调节因子和重要的治疗靶点。为了解决这一假设，我们提出：(1)确定介导Gfi1/1b促肿瘤作用的辅助因子和转录靶点；(2)确定Gfi1和Gfi1b是否需要维持肿瘤；(3)确定抑制gfi1 /1b激活肿瘤生长的治疗剂。拟议的研究将提供新的、遗传相关的3mb组肿瘤发生的分子机制，并有助于确定治疗该疾病的新靶点。

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have divided MB into four molecular subgroups: WNT, SHH, Group 3, and Group 4. While WNT and SHH tumors have a relatively favorable prognosis, Group 3 tumors (characterized by overexpression of the MYC oncogene) are much more aggressive and almost invariably fatal. The first mouse model of Group 3 MB was recently established in our lab by infecting neural stem cells (NSCs) with viruses encoding Myc and a dominant- negative form of the p53 tumor suppressor (DNp53), and then transplanting these cells back into the cerebellum of immunodeficient mice. Although the resulting tumors resemble human Group 3 MB, this model does not precisely recapitulate the genetics of the human disease, as most human Group 3 tumors do not exhibit mutation or loss of p53. Thus, a major goal of our research has been to identify second hits that can cooperate with MYC and are relevant to human MB. Recent whole genome sequencing analysis has identified two chromosomal loci that are hotspots for rearrangement in Group 3 MB. Rearrangements at these loci activate the zinc-finger transcriptional repressors Gfi1 and Gfi1b. Importantly, our preliminary data show that both Gfi1 and Gfi1b can cooperate with Myc to drive MB formation in mice. Based on the striking prevalence of these events in human Group 3 MB as well as previous reports that Gfi1 cooperates with Myc in leukemia, we hypothesize that Gfi proteins are key regulators of tumorigenesis and important therapeutic targets in Group 3 MB. To address this hypothesis, we propose to (1) Identify the cofactors and transcriptional targets that mediate the tumor-promoting effects of Gfi1/1b, (2) Determine if Gfi1 and Gfi1b are required for tumor maintenance, and (3) Identify therapeutic agents that inhibit the growth of Gfi1/1b-activated tumors. The proposed studies will provide insight into the molecular mechanisms of tumorigenesis in new, genetically- relevant models of Group 3 MB and help identify novel targets for therapy of this disease.