Isocitrate dehydrogenase (IDH) mutant gliomas are the most common brain tumors affecting young adults. IDH mutations give rise to an oncometabolite – D-2-hydroxyglutarate (D-2HG) – that inhibits DNA demethylases, initiating a cascade of epigenetic dysregulation and aberrant oncogene activation. Although most IDH-mutant gliomas are diagnosed as low-grade tumors, growing slowly over many years, they eventually transform into aggressive, high-grade tumors that lead to progressive disability and eventual death.

 In our study, we apply single-cell methods to characterize both the gene expression and chromatin accessibility profiles of individual tumor cells sourced from high- and low-grade tumors. Comparing malignant cells to normal cells from developing and adult brains, we highlight the parallelism between malignant cell states and developmental cell types. Taking stock of the diversity of cell states in tumors, we observe that while low-grade tumors are composed predominantly of oligodendrocyte-like progenitors (OPCs) and astrocyte-like cells (ACs), with grade progression tumors become enriched with highly proliferative neural progenitor-like cells (NPCs). However, we note that unlike in normal cell progenitors, where chromatin accessibility is clearly defined, patterns of chromatin accessibility overlap for different malignant cell states, consistent with a more permissive epigenetic background that favors cellular plasticity.

 We found a mechanism that favors the expansion of the NPC cells with increasing tumor grade has to do with the suppression of interferon signaling activation. In high-grade tumors, the deletion of cell cycle regulators in chromosome 9 goes along with the deletion of interferon gene loci. This absence of interferon signaling protects NPC cells from differentiating into less proliferative cell states, as well as decreases immune activation against the tumor. In low-grade tumors, interferon signaling is prevented through a different mechanism. The hypermethylation induced by D-2HG silences the expression of transposable elements that are implicated in the activation of interferon signaling. By treating patient-derived IDH-mutant glioma organoid models with a demethylating agent, we show an increase in the expression of transposable elements and downstream interferon gene expression, as well as a reduction in the proportion of NPC cells in the tumor.

Fig. IDH-mutant gliomas initiate through the transformation of OPC cells (blue) to slow-growing OPC-like malignant cells (purple) driven by epigenetic changes involving DNA hypermethylation. During tumor progression, OPC-like cells partially reprogram to proliferative NPC-like cells (red) that lose their hypermethylation and become dependent on genetic drivers.

Although IDH-mutant gliomas are classified into three different grades – 2, 3, and 4 – our study highlights that there are essentially 2 phases in the natural history of these tumors: one characterized by a hypermethylated state that enables aberrant oncogene expression and suppression of interferon signaling by epigenetic dysregulation; and one resulting from the accumulation of successive genetic alterations that give rise to epigenetic-independent oncogenic activity and interferon silencing.

 Our findings provide additional rationale for the approach of treating IDH-mutant gliomas in their initial epigenetic phase – with the use of IDH inhibitors, alone or in combination with demethylating agents – with the goal of stabilizing tumors in a less proliferative state and averting the genetic progression seen in high-grade disease as we evidence in our study.

Link to the paper: https://www.nature.com/articles/s43018-024-00865-3