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Research Brief

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

Lynn Bjerke, Alan Mackay, Meera Nandhabalan, Anna Burford, Alexa Jury, Sergey Popov, Dorine A. Bax, Diana Carvalho, Kathryn R. Taylor, Maria Vinci, Ilirjana Bajrami, Imelda M. McGonnell, Christopher J. Lord, Rui M. Reis, Darren Hargrave, Alan Ashworth, Paul Workman and Chris Jones
Lynn Bjerke
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Alan Mackay
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Meera Nandhabalan
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Anna Burford
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Alexa Jury
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Sergey Popov
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Dorine A. Bax
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Diana Carvalho
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Kathryn R. Taylor
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Maria Vinci
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Ilirjana Bajrami
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Imelda M. McGonnell
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Christopher J. Lord
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Rui M. Reis
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Darren Hargrave
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Alan Ashworth
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Paul Workman
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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Chris Jones
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
1Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil
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DOI: 10.1158/2159-8290.CD-12-0426 Published May 2013
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  • Figure 1.
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    Figure 1.

    Distinct molecular and clinical correlates of H3F3A mutation subgroups. A, heatmap representing differential gene expression signatures between G34 versus K27, and G34 versus wild-type, pediatric GBM specimens identified by Paugh and colleagues (3). Top 100 differentially expressed genes are shown for each comparison. B, gene set enrichment analysis (GSEA) for differential gene expression signatures identified by Schwartzentruberand colleagues (2) versus those from Paugh and colleagues (3). Top, G34 versus K27: enrichment score (ES) = 0.833, P [family-wise error rate (FWER)] = 0.0, q [false discovery rate (FDR)] = 0.0. Bottom, G34 versus wild-type: ES = 0.94, FWER P = 0.0, FDR q = 0.0. C, heatmap representing differential gene expression signatures between G34 versus K27, and G34 versus wild-type, pediatric GBM specimens from (2). Top 100 differentially expressed genes are shown for each comparison. D, GSEA for differential gene expression signatures identified in (3) versus those in (2). Top, G34 versus K27: ES = 0.88, FWER P = 0.03, FDR q = 0.04. Bottom, G34 versus wild-type: ES = 0.90, FWER P = 0.0, FDR q = 0.0. E, hierarchical clustering of the integrated gene expression datasets, highlighting specific clusters of G34- and K27-mutant tumors, distinct from a more heterogeneous group of wild-type cases. G34V tumors are represented by asterisks. F, K-means consensus clustering finds the most stable number of subgroups to be 3, marked by H3F3A mutation status. G, K27- and G34-mutant pediatric GBM in our integrated dataset have distinct age incidence profiles, with K27 tumors peaking at 7 years in contrast to G34 at age 14. The 2 G34V tumors were diagnosed at age 14 and 20. H, Kaplan–Meier plot for overall survival of pediatric patients with GBM stratified by H3F3A status. K27-mutant tumors have significantly shorter survival than G34 (P = 0.0164, log-rank test). A single G34V case for which data were available had an overall survival of 1.4 years. wt, wild-type.

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    Figure 2.

    Differential binding of H3K36me3 in G34-mutant KNS42 cells drives pediatric GBM expression signatures. A, Sanger sequencing trace for KNS42 pediatric GBM cells reveals a heterozygous c.104G>T p.(Gly34Val) H3F3A mutation. B, Western blot analysis for mono-(me1), di-(me2), and tri-(me3) methylated histone H3 in G34-mutant KNS42 and wild-type (wt) pediatric glioma cell lines. Total H3 is used as an extracted histone loading control. C, Circos plot representing the KNS42 genome, aligned with chromosomes 1 to X running clockwise from 12 o'clock. Outer ring, H3K36me3 ChIP-Seq binding. Gray, all binding; blue, differential binding in KNS42 versus SF188. Selected differentially bound developmental transcription factors and pluripotency genes are labeled. Inner ring, DNA copy number. Green points, copy number gain; black points, normal copy number; red points, copy number loss. Single base mutations in selected genes (H3F3A:G34V and TP53:R342*) are labeled inside the circle. D, correlation plot of RNA polymerase II versus H3K36me3 for 65 differentially trimethyl-bound regions by ChIP-Seq in KNS42 cells. R2 = 0.66; P < 0.0001. E, heatmap representing a ranked list of differentially bound H3K36me3 and RNA polymerase II in G34V KNS42 versus wild-type SF188 cells, with top 20 genes listed. F, GSEA for preranked differentially bound genes identified in ChIP-Seq versus those in the integrated gene expression datasets. Top, G34 versus K27: ES = 0.86, FWER P = 0.03, FDR q = 0.03. Bottom, G34 versus wild-type: ES = 0.84, FWER P = 0.02, FDR q = 0.04. G, DAVID gene ontology analysis for preranked list of differentially bound genes identified in ChIP-Seq. Fold enrichment of processes are plotted and colored by FDR q value. H, top, mean expression of the G34 core enrichment signature in a temporal gene expression dataset of human brain development. Period 1, embryonal; periods 2–7, fetal; periods 8–12, postnatal; periods 13–15, adulthood. Bottom, heatmap representing spatial differences in G34 core enrichment signature expression in structures within embryonic and early fetal development, with highest levels mapping to the ganglionic eminences and amygdala.

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    Figure 3.

    G34 induces a transcriptional program linked to forebrain development and self-renewal. A, ChIP-Seq of H3K36me3 and RNA polymerase II binding for G34-mutant KNS42 (blue) and wild-type (wt) SF188 cells (gray) for the DLX6 locus, which also encompasses the transcripts DLX5, DLX6-AS1, and DLX6-AS2. B, validation of ChIP-Seq data by ChIP-qPCR using specific primers targeting DLX6. Blue bars, KNS42; gray, SF188. ***, P < 0.0001, t test. C, boxplot of DLX6 expression in the integrated pediatric GBM samples stratified by H3F3A status. Blue box, G34; green, K27; gray, wild-type. ***, P < 0.001, ANOVA. D, top, immunohistochemistry for DLX6 protein in a G34 mutant pediatric GBM sample RMH2465. Bottom, barplot of DLX6 expression in a pediatric GBM tissue microarray stratified by H3F3A status. Blue bars, G34; green, K27; gray, wild-type. ++, strong expression; +, moderate expression; −, negative. E, ChIP-Seq of H3K36me3 and RNA polymerase II binding for G34-mutant KNS42 (blue) and wild-type SF188 cells (gray) for the SOX2 locus, which also encompasses the SOX2-OT transcript. F, validation of ChIP-Seq data by ChIP-qPCR using specific primers targeting SOX2. Blue bars, KNS42; gray, SF188. ***, P < 0.0001, t test. G, boxplot of SOX2 expression in the integrated pediatric GBM samples stratified by H3F3A status. Blue box, G34; green, K27; gray, wild-type. *, P < 0.05, ANOVA. H, top, immunohistochemistry for SOX2 protein in a G34-mutant pediatric GBM sample RMH2465. Bottom, barplot of SOX2 expression in a pediatric GBM tissue microarray stratified by H3F3A status. Blue bars, G34; green, K27; gray, wild-type. ++, strong expression; +, moderate expression; −, negative.

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    Figure 4.

    G34 H3K36me3 upregulates MYCN which is selectively targetable by kinases that destabilize the protein. A, ChIP-Seq of H3K36me3 and RNA polymerase II binding for G34-mutant KNS42 (blue) and wild-type (wt) SF188 cells (gray) for the MYCN locus, which also encompasses the MYCNOS transcript. B, validation of ChIP-Seq data by ChIP-qPCR using specific primers targeting MYCN. Blue bars, KNS42; gray, SF188. ***, P < 0.0001, t test. C, boxplot of MYCN expression in the integrated pediatric GBM samples stratified by H3F3A status. Blue box, G34; green, K27; gray, wild-type. **, P < 0.01, ANOVA. Wild-type tumors with high mRNA expression were frequently amplified (Amp). D, top, immunohistochemistry for MYCN protein in a G34-mutant pediatric GBM sample. RMH2465 bottom, barplot of MYCN expression in a pediatric GBM tissue microarray stratified by H3F3A status. Blue bars, G34; green, K27; gray, wild-type. ++, strong expression; +, moderate expression; −, negative. E, effects on cell viability of MYCN knockdown in KNS42 cells. Western blot analysis showing efficiency of reduction of MYCN by 3 individual siRNAs targeting MYCN (named 6, 12, and W) and a pool of all 3 after 48 and 96 hours. Barplot showing effects on KNS42 cell viability after siRNA knockdown at 7 days. ***, P < 0.001, t test versus control. F, siRNA screen for 714 human kinases in KNS42 cells. Western blot analysis showing expression of MYCN protein in G34-mutant KNS42 cells in contrast to a panel of wild-type pediatric glioma lines. GAPDH is used as a loading control. Kinase targets are plotted in plate well order along the x-axis, and Z scores along the y-axis. PLK1 is used as a positive control and is plotted in red. Negative controls are colored light gray, and kinases with Z scores greater than −2.0 (no effect on cell viability) are colored gray. “Hits” (Z score < −2.0) are colored dark gray or blue, the latter if the effect on cell viability is specific to KNS42 cells and not in a panel of 4 H3F3A wild-type pediatric glioma cell lines. The most significant and selective hits were for CHK1 and AURKA. G, effect of knockdown of AURKA on MYCN levels in KNS42 cells. Western blot analysis for AURKA and MYCN in KNS42 cells treated with individual oligonucleotides directed against AURKA for 48 and 96 hours. GAPDH is used as a loading control. H, effect of a selective small-molecule inhibitor of AURKA on MYCN protein levels and cell viability. Left, Western blot analysis for MYCN protein in KNS42 cells after exposure to 0.1, 0.5, and 2 to 5 μmol/L VX-689 (triangle). GAPDH is used as a loading control. Right, barplot showing effects on cell viability of KNS42 cells exposed to 0.1, 0.5, and 2 to 5 μmol/L VX-689. **, P < 0.01, t test versus control.

Additional Files

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    Files in this Data Supplement:

    • Supplementary Methods - PDF file - 120K
    • Supplementary Figure Legends - PDF file - 139K
    • Supplementary Figures 1 - 13 - PDF file - 495K, Collated supplementary figures. S1 - Expression of histone H3 methylation marks in paediatric glioma and normal cell lines. S2 - Further characterisation of KNS42 cells. S3 - H3K36me3 binding in H3F3A wild-type SF188 paediatric GBM cells. S4 -Spatio-temporal gene expression of H3F3A mutation-specific signatures in the human brain S5-S12 - Validation of differential H3K36me3 binding and expression of developmental transcription factors and genes associated with stem cell maintenance and pluripotency S13 - MYCN expression in G34V isogenic cells
    • Supplementary Table 1 - PDF file - 12611K, Datasets used for gene expression profiling analysis.
    • Supplementary Table 2 - XLSX file - 1310K, Differentially bound ChIP-Seq regions and genes in paediatric GBM cells.
    • Supplementary Table 3 - XLSX file - 33K, Core enrichment of genes between differential expression analysis in primary tumours and ChIP-Seq in paediatric GBM cells.
    • Supplementary Table 4 - PDF file - 32K, Paediatric GBM tissue microarray samples.
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Cancer Discovery: 3 (5)
May 2013
Volume 3, Issue 5
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Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
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Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
Lynn Bjerke, Alan Mackay, Meera Nandhabalan, Anna Burford, Alexa Jury, Sergey Popov, Dorine A. Bax, Diana Carvalho, Kathryn R. Taylor, Maria Vinci, Ilirjana Bajrami, Imelda M. McGonnell, Christopher J. Lord, Rui M. Reis, Darren Hargrave, Alan Ashworth, Paul Workman and Chris Jones
Cancer Discov May 1 2013 (3) (5) 512-519; DOI: 10.1158/2159-8290.CD-12-0426

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Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
Lynn Bjerke, Alan Mackay, Meera Nandhabalan, Anna Burford, Alexa Jury, Sergey Popov, Dorine A. Bax, Diana Carvalho, Kathryn R. Taylor, Maria Vinci, Ilirjana Bajrami, Imelda M. McGonnell, Christopher J. Lord, Rui M. Reis, Darren Hargrave, Alan Ashworth, Paul Workman and Chris Jones
Cancer Discov May 1 2013 (3) (5) 512-519; DOI: 10.1158/2159-8290.CD-12-0426
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Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

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