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The authors declare that there is no conflict of interest regarding the publication of this article. Word count: 5451Total number of figure and tables: 6 main figures; 11 supplemental figures and 1 supplemental table.

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

Diffuse intrinsic pontine glioma (DIPG) is a rare but deadly pediatric brainstem tumor. To date, there is no effective therapy for DIPG. Transcriptomic analyses have revealed DIPGs have a distinct profile from other pediatric high-grade gliomas occurring in the cerebral hemispheres. These unique genomic characteristics coupled with the younger median age group suggest that DIPG has a developmental origin. The most frequent mutation in DIPG is a lysine to methionine (K27M) mutation that occurs on H3F3A and HIST1H3B/C, genes encoding histone variants. The K27M mutation disrupts methylation by polycomb repressive complex 2 on histone H3 at lysine 27, leading to global hypomethylation. Histone 3 lysine 27 trimethylation is an important developmental regulator controlling gene expression. This review discusses the developmental and epigenetic mechanisms driving disease progression in DIPG, as well as the profound therapeutic implications of epigenetic programming.

Brief Summary: Inhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity. Abstract:Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas.Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q codeletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, relates to the gliomas' subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8 + T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients. Introduction:Gliomas are highly infiltrative brain tumors accounting for 32% of all primary central nervous system malignancies (1). With advances in molecular biology and sequencing technologies, a distinct profile of genetic alterations for gliomas has emerged (1-3). A gain-offunction mutation in the gene encoding isocitrate dehydrogenase 1 (IDH1) mutation has been reported in ~46% of all adult gliomas (2) and ~80% of low grade gliomas (3, 4). This mutation results in the replacement of arginine (R) for histidine (H) at amino acid residue 132 (R132H) (5, 6). In gliomas, the IDH1-R132H mutation co-occurs with the following genetic alterations: i) oligodendroglioma-1p/19q co-deletion, TERT promoter mutations, or ii) astrocytoma-inactivation of tumor suppressor protein 53 (TP53) gene and loss of function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX) (2, 4, 7).The IDH1-R132H neomorphic mutation (mIDH1) confers a gain-of-function catalytic activity, prompting the NADPH-dependent reduction of alpha ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (2-HG) (5, 8,9). The accumulation of 2-HG acts antagonistically to α-KG, competitively inhibiting α-KG-dependent dioxygenases, including the ten-eleven translocation (TET) methylcytosine dioxygenases and Jumonji C (JmjC)...