Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN

Abstract

Glioblastomas of children and young adults have a median survival of only 12-15months and are clinically and biologically distinct from histologically similar cancers in older adults1. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A2, occurring either at or close to key residues marked by methylation for regulation of transcription – K27 and G34. Here we show that the cerebral hemispheric-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem cell maintenance, cell fate decisions and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene which is causative of glioblastomas when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population by inhibiting kinases responsible for stabilisation of the protein.

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…Recently, genome-wide methylation analysis of both adult and pediatric glioblastoma multiforme identified recurrent functional mutations in the epigenetic modulator histone 3 gene (H3F3A; ref. 23), resulting in enhanced transcription of N-myc, which, in turn, promotes proliferation and suppresses differentiation (24). Therefore, targeting H3F3A-mutant tumors using therapeutic approaches to target N-myc may represent a novel therapeutic approach for a distinct subset of glioblastoma multiforme.…”

“…AURKA inhibitors have shown preclinical activity in N-myc-amplified neuroblastoma and neuroendocrine prostate cancer (35,66,88), and are now undergoing phase II evaluation for these diseases. Recently, Bjerke and colleagues carried out a synthetic lethal screen to identify kinases that could represent a therapeutic target in N-myc-amplified pediatric glioblastoma multiforme (24). Out of 714 kinases tested, knockdown of CHK1 (checkpoint kinase 1) or AURKA promoted N-myc stability and reduced viability in N-myc-amplified cells.…”

In silico analysis of histone H3 gene expression during human brain development

“…Notably, recurrent mutations in H3F3A converting Glycine (G)-34 to arginine (R) or valine (V) were also identified in multiple cases of GBM/NB-PG (Schwartzentruber et al, 2012;Wu et al, 2012). These contribute to cancer progression in pathway(s) distinct from disruption of H3K27 methylation and PRC2 function (Bjerke et al, 2013). Unlike H3F3AK27M and HIST1H3BK27M, which are associated with the brainstem and thalamus, the H3F3AG34R/V mutations were preferential to cases affecting brain structures outside of the brainstem , and did not show the striking association with pediatric cases seen for H3F3AK27M (Schwartzentruber et al, 2012).…”

Histone Variant H3.3: A versatile H3 variant in health and in disease

“…This result indicates that H3K36me3 is regulated indirectly through Gly34, possibly because it is involved in the recruitment of methyltransferase. Surprisingly, in pediatric GBM tumors, H3K36me3 and Pol II were found aberrantly enriched within genic regions of several key transcription factors, including MYCN, Sox2 and DLX6, which may be involved in the elevated transcription of these genes, thus resulting in the reprogramming of the transcriptional states of the tumor towards an earlier developmental stage (Bjerke et al, 2013). Taken together, H3.3 mutations can promote pHGGs tumorigenesis via a hijacking H3K36me3 pathway either directly (K36M mutation) or indirectly (G34R/V/W/L mutations), thus functioning within a specific tissue environment.…”