HOXA5 is a survival locus associated with chromosome 7 gain in IDH-wildtype glioblastoma

Glioblastomas (GBMs) are divided into CpG Island Methylator Phenotype (CIMP) and non-CIMP tumors. Non-CIMP GBMs derive from cells with non-disjunction of chromosome (chr7) and chromosome 10 (chr10), resulting in chr7 gain and chr10 loss, while CIMP GBMs have mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2). Gain of chr7 is largely driven by PDGFA, but other genes on chr7 are likely to contribute to fitness gains and aggressiveness of these GBMs. We computationally investigated genes on chr7 whose gene expression correlated with survival, identifying HOXA5 as a potential driver of proneural gliomagenesis. Using a combination of human GBM cells and mouse PDGF-driven gliomas, we showed that HOXA5 drives increased proliferation and radiation resistance in culture and in vivo. These phenotypes appear to be in part due to effects on p53 and other apoptosis-related genes. In order to determine whether elevated HOXA5 gene expression is causally related to aggressiveness of non-CIMP PN GBM, we used a PDGF-driven PN GBM mouse model based on the RCAS/tva system to perform gain of function analysis for HOXA5.

胶质母细胞瘤（Glioblastomas, GBMs）可分为CpG岛甲基化表型（CpG Island Methylator Phenotype, CIMP）亚型与非CIMP亚型肿瘤。非CIMP型胶质母细胞瘤起源于染色体7（chromosome 7, chr7）与染色体10（chromosome 10, chr10）发生不分离的细胞，进而导致chr7拷贝数获得、chr10拷贝数缺失；而CIMP型胶质母细胞瘤则存在异柠檬酸脱氢酶1或2（isocitrate dehydrogenase 1 or 2, IDH1/2）突变。chr7的拷贝数获得主要由血小板源性生长因子A（PDGFA）驱动，但chr7上的其他基因可能同样有助于这类胶质母细胞瘤的适应性提升与侵袭性增强。本研究通过计算生物学方法分析了chr7上与患者总生存期相关的基因，鉴定出HOXA5作为神经前体型胶质瘤发生的潜在驱动因子。随后结合人类胶质母细胞瘤细胞与小鼠血小板源性生长因子（PDGF）诱导的胶质瘤模型，我们证实HOXA5可在体外与体内促进细胞增殖并增强辐射抗性。上述表型在一定程度上归因于HOXA5对p53及其他凋亡相关基因的调控作用。为明确HOXA5基因表达上调是否与非CIMP型神经前体胶质母细胞瘤的侵袭性存在因果关联，我们采用基于RCAS/tva系统的PDGF诱导型神经前体胶质母细胞瘤小鼠模型，对HOXA5开展功能获得性分析。