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

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. Overall design: 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.