Glioma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase (IDH) mutations in up to 80% lower grade gliomas (LGG) and in 76% secondary glioblastomas (GBM). IDH mutations are also seen in 10%–20% of acute myeloid leukemia (AML). In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells (pre-LSCs) stage, whereas mutations in genes propagating oncogenic signal are late events in leukemia. IDH mutations are also early events in glioma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in glioma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD4 as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK4, FIP1L1, or FUBP1 collaborate with IDH mutations to negatively affect patients’ survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4 at genetic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and glioma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premalignant stem cells to glioma.