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Oncohistones and disrupted development in pediatric-type diffuse high-grade glioma

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Abstract

Recurrent, clonal somatic mutations in histone H3 are molecular hallmarks that distinguish the genetic mechanisms underlying pediatric and adult high-grade glioma (HGG), define biological subgroups of diffuse glioma, and highlight connections between cancer, development, and epigenetics. These oncogenic mutations in histones, now termed “oncohistones”, were discovered through genome-wide sequencing of pediatric diffuse high-grade glioma. Up to 80% of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) and diffuse glioma arising in other midline structures including thalamus or spinal cord, contain histone H3 lysine 27 to methionine (K27M) mutations or, rarely, other alterations that result in a depletion of H3K27me3 similar to that induced by H3 K27M. This subgroup of glioma is now defined as diffuse midline glioma, H3K27-altered. In contrast, histone H3 Gly34Arg/Val (G34R/V) mutations are found in approximately 30% of diffuse glioma arising in the cerebral hemispheres of older adolescents and young adults, now classified as diffuse hemispheric glioma, H3G34-mutant. Here, we review how oncohistones modulate the epigenome and discuss the mutational landscape and invasive properties of histone mutant HGGs of childhood. The distinct mechanisms through which oncohistones and other mutations rewrite the epigenetic landscape provide novel insights into development and tumorigenesis and may present unique vulnerabilities for pHGGs. Lessons learned from these rare incurable brain tumors of childhood may have broader implications for cancer, as additional high- and low-frequency oncohistone mutations have been identified in other tumor types.

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References

  1. Ostrom, Q.T., Price, M., Ryan, K., Edelson, J., Neff, C., Cioffi, G., et al. (2022). CBTRUS statistical report: pediatric brain tumor foundation childhood and adolescent primary brain and other central nervous system tumors diagnosed in the United States in 2014–2018. NLM (Medline), iii1–iii38. https://doi.org/10.1093/neuonc/noac161

  2. Pajtler, K. W., Wen, J., Sill, M., Lin, T., Orisme, W., Tang, B., et al. (2018). Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathologica, 136(2), 211–226. https://doi.org/10.1007/s00401-018-1877-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schwartzentruber, J., Korshunov, A., Liu, X. Y., Jones, D. T., Pfaff, E., Jacob, K., et al. (2012). Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature, 482(7384), 226–31. https://doi.org/10.1038/nature10833

    Article  CAS  PubMed  Google Scholar 

  4. Sturm, D., Witt, H., Hovestadt, V., Khuong-Quang, D. A., Jones, D. T., Konermann, C., et al. (2012). Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell, 22(4), 425–437. https://doi.org/10.1016/j.ccr.2012.08.024

    Article  CAS  PubMed  Google Scholar 

  5. Wu, G., Broniscer, A., McEachron, T. A., Lu, C., Paugh, B. S., Becksfort, J., et al. (2012). Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genetics, 44(3), 251–253. https://doi.org/10.1038/ng.1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ceccarelli, M., Barthel, F. P., Malta, T. M., Sabedot, T. S., Salama, S. R., Murray, B. A., et al. (2016). Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell, 164(3), 550–563. https://doi.org/10.1016/j.cell.2015.12.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mackay, A., Burford, A., Carvalho, D., Izquierdo, E., Fazal-Salom, J., Taylor, K. R., et al. (2017). Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell, 32(4), 520-537 e5. https://doi.org/10.1016/j.ccell.2017.08.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mendiratta, S., Gatto, A., & Almouzni, G. (2019). Histone supply: Multitiered regulation ensures chromatin dynamics throughout the cell cycle. Journal of Cell Biology, 218(1), 39–54. https://doi.org/10.1083/jcb.201807179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Talbert, P.B. and Henikoff, S. (2021). Histone variants at a glance. Journal of Cell Science, 134(6). https://doi.org/10.1242/jcs.244749

  10. Filipescu, D., Muller, S., & Almouzni, G. (2014). Histone H3 variants and their chaperones during development and disease: Contributing to epigenetic control. Annual Review of Cell and Developmental Biology, 30, 615–646. https://doi.org/10.1146/annurev-cellbio-100913-013311

    Article  CAS  PubMed  Google Scholar 

  11. Lewis, P.W., Elsaesser, S.J., Noh, K.M., Stadler, S.C., and Allis, C.D. (2010). Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proceedings of the National Academy of Sciences, 107(32):14075–80. https://doi.org/10.1073/pnas.1008850107

  12. Amorim, J.P., Santos, G., Vinagre, J., and Soares, P. (2016). The Role of ATRX in the Alternative Lengthening of Telomeres (ALT) Phenotype. Genes (Basel), 7(9). https://doi.org/10.3390/genes7090066

  13. Lovejoy, C. A., Li, W., Reisenweber, S., Thongthip, S., Bruno, J., de Lange, T., et al. (2012). Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet, 8(7), e1002772. https://doi.org/10.1371/journal.pgen.1002772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ray-Gallet, D. and Almouzni, G. (2019). Histone Mutations and Cancer. 17–42

  15. Khuong-Quang, D. A., Buczkowicz, P., Rakopoulos, P., Liu, X. Y., Fontebasso, A. M., Bouffet, E., et al. (2012). K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathological, 124(3), 439–47. https://doi.org/10.1007/s00401-012-0998-0

    Article  CAS  Google Scholar 

  16. Ren, M., & Van Nocker, S. (2016). In silico analysis of histone H3 gene expression during human brain development (pp. 167–173). University of the Basque Country Press.

    Google Scholar 

  17. Wu, G., Diaz, A. K., Paugh, B. S., Rankin, S. L., Ju, B., Li, Y., et al. (2014). The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics, 46(5), 444–450. https://doi.org/10.1038/ng.2938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fontebasso, A. M., Papillon-Cavanagh, S., Schwartzentruber, J., Nikbakht, H., Gerges, N., Fiset, P. O., et al. (2014). Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nature Genetics, 46(5), 462–466. https://doi.org/10.1038/ng.2950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Buczkowicz, P., Hoeman, C., Rakopoulos, P., Pajovic, S., Letourneau, L., Dzamba, M., et al. (2014). Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nature Genetics, 46(5), 451–456. https://doi.org/10.1038/ng.2936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Karremann, M., Gielen, G. H., Hoffmann, M., Wiese, M., Colditz, N., Warmuth-Metz, M., et al. (2018). Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neuro-Oncology, 20(1), 123–131. https://doi.org/10.1093/neuonc/nox149

    Article  CAS  PubMed  Google Scholar 

  21. Chen, C. C. L., Deshmukh, S., Jessa, S., Hadjadj, D., Lisi, V., Andrade, A. F., et al. (2020). Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis. Cell, 183(6), 1617–1633. https://doi.org/10.1016/j.cell.2020.11.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Guerreiro Stucklin, A. S., Ryall, S., Fukuoka, K., Zapotocky, M., Lassaletta, A., Li, C., et al. (2019). Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nature Communications, 10(1), 4343. https://doi.org/10.1038/s41467-019-12187-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Korshunov, A., Ryzhova, M., Hovestadt, V., Bender, S., Sturm, D., Capper, D., et al. (2015). Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathologica, 129(5), 669–678. https://doi.org/10.1007/s00401-015-1405-4

    Article  CAS  PubMed  Google Scholar 

  24. Mackay, A., Burford, A., Molinari, V., Jones, D. T. W., Izquierdo, E., Brouwer-Visser, J., et al. (2018). Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell, 33(5), 829-842 e5. https://doi.org/10.1016/j.ccell.2018.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Korshunov, A., Capper, D., Reuss, D., Schrimpf, D., Ryzhova, M., Hovestadt, V., et al. (2016). Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathologica, 131(1), 137–146. https://doi.org/10.1007/s00401-015-1493-1

    Article  CAS  PubMed  Google Scholar 

  26. Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., et al. (2009). IDH1 and IDH2 mutations in gliomas. New England Journal of Medicine, 360(8), 765–773. https://doi.org/10.1056/NEJMoa0808710

    Article  CAS  PubMed  Google Scholar 

  27. Clarke, M., Mackay, A., Ismer, B., Pickles, J. C., Tatevossian, R. G., Newman, S., et al. (2020). Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discovery, 10(7), 942–963. https://doi.org/10.1158/2159-8290.CD-19-1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Korshunov, A., Schrimpf, D., Ryzhova, M., Sturm, D., Chavez, L., Hovestadt, V., et al. (2017). H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathologica, 134(3), 507–516. https://doi.org/10.1007/s00401-017-1710-1

    Article  CAS  PubMed  Google Scholar 

  29. Bender, S., Tang, Y., Lindroth, A. M., Hovestadt, V., Jones, D. T., Kool, M., et al. (2013). Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell, 24(5), 660–672. https://doi.org/10.1016/j.ccr.2013.10.006

    Article  CAS  PubMed  Google Scholar 

  30. Chan, K. M., Fang, D., Gan, H., Hashizume, R., Yu, C., Schroeder, M., et al. (2013). The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes & Development, 27(9), 985–90. https://doi.org/10.1101/gad.217778.113

    Article  CAS  Google Scholar 

  31. Venneti, S., Garimella, M. T., Sullivan, L. M., Martinez, D., Huse, J. T., Heguy, A., et al. (2013). Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathology, 23(5), 558–564. https://doi.org/10.1111/bpa.12042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lewis, P. W., Muller, M. M., Koletsky, M. S., Cordero, F., Lin, S., Banaszynski, L. A., et al. (2013). Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science, 340(6134), 857–861. https://doi.org/10.1126/science.1232245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Diehl, K.L., Ge, E.J., Weinberg, D.N., Jani, K.S., Allis, C.D., and Muir, T.W. (2019). PRC2 engages a bivalent H3K27M-H3K27me3 dinucleosome inhibitor. Proceedings of the National Academy of Sciences, 116(44), 22152-22157https://doi.org/10.1073/pnas.1911775116

  34. Fang, D., Gan, H., Cheng, L., Lee, J.H., Zhou, H., Sarkaria, J.N., et al. (2018). H3.3K27M mutant proteins reprogram epigenome by sequestering the PRC2 complex to poised enhancers. Elife, 7. https://doi.org/10.7554/eLife.36696

  35. Piunti, A., Hashizume, R., Morgan, M. A., Bartom, E. T., Horbinski, C. M., Marshall, S. A., et al. (2017). Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nature Medicine, 23(4), 493–500. https://doi.org/10.1038/nm.4296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Joshi, A., Miller, C., Jr., Baker, S. J., & Ellenson, L. H. (2015). Activated mutant p110alpha causes endometrial carcinoma in the setting of biallelic Pten deletion. American Journal of Pathology, 185(4), 1104–1113. https://doi.org/10.1016/j.ajpath.2014.12.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Justin, N., Zhang, Y., Tarricone, C., Martin, S. R., Chen, S., Underwood, E., et al. (2016). Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nature Communications, 7, 11316. https://doi.org/10.1038/ncomms11316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stafford, J. M., Lee, C. H., Voigt, P., Descostes, N., Saldana-Meyer, R., Yu, J. R., et al. (2018). Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma. Science Advances, 4(10), eaau5935. https://doi.org/10.1126/sciadv.aau5935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lee, C. H., Yu, J. R., Granat, J., Saldana-Meyer, R., Andrade, J., LeRoy, G., et al. (2019). Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma. Genes & Development, 33(19–20), 1428–1440. https://doi.org/10.1101/gad.328773.119

    Article  CAS  Google Scholar 

  40. Sarthy, J.F., Meers, M.P., Janssens, D.H., Henikoff, J.G., Feldman, H., Paddison, P.J., et al. (2020). Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones. Elife, 9. https://doi.org/10.7554/eLife.61090

  41. Wang, X., Long, Y., Paucek, R. D., Gooding, A. R., Lee, T., Burdorf, R. M., et al. (2019). Regulation of histone methylation by automethylation of PRC2. Genes & Development, 33(19–20), 1416–1427. https://doi.org/10.1101/gad.328849.119

    Article  CAS  Google Scholar 

  42. Harutyunyan, A. S., Krug, B., Chen, H., Papillon-Cavanagh, S., Zeinieh, M., De Jay, N., et al. (2019). H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis. Nature Communications, 10(1), 1262. https://doi.org/10.1038/s41467-019-09140-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, J., Ding, L., Holmfeldt, L., Wu, G., Heatley, S. L., Payne-Turner, D., et al. (2012). The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature, 481(7380), 157–163. https://doi.org/10.1038/nature10725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brien, G. L., Bressan, R. B., Monger, C., Gannon, D., Lagan, E., Doherty, A. M., et al. (2021). Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3–K27M oncogenic activity in human hindbrain neural stem cells. Nature Genetics, 53(8), 1221–1232. https://doi.org/10.1038/s41588-021-00897-w

    Article  CAS  PubMed  Google Scholar 

  45. Larson, J. D., Kasper, L. H., Paugh, B. S., Jin, H., Wu, G., Kwon, C. H., et al. (2019). Histone H3.3 K27M Accelerates Spontaneous Brainstem Glioma and Drives Restricted Changes in Bivalent Gene Expression. Cancer Cell, 35(1), 140-155 e7. https://doi.org/10.1016/j.ccell.2018.11.015

    Article  CAS  PubMed  Google Scholar 

  46. Mohammad, F., Weissmann, S., Leblanc, B., Pandey, D. P., Hojfeldt, J. W., Comet, I., et al. (2017). EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nature Medicine, 23(4), 483–492. https://doi.org/10.1038/nm.4293

    Article  CAS  PubMed  Google Scholar 

  47. Wagner, E. J., & Carpenter, P. B. (2012). Understanding the language of Lys36 methylation at histone H3. Nature Reviews Molecular Cell Biology, 13(2), 115–126. https://doi.org/10.1038/nrm3274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schmitges, F. W., Prusty, A. B., Faty, M., Stutzer, A., Lingaraju, G. M., Aiwazian, J., et al. (2011). Histone methylation by PRC2 is inhibited by active chromatin marks. Molecular Cell, 42(3), 330–341. https://doi.org/10.1016/j.molcel.2011.03.025

    Article  CAS  PubMed  Google Scholar 

  49. Yuan, W., Xu, M., Huang, C., Liu, N., Chen, S., & Zhu, B. (2011). H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. Journal of Biological Chemistry, 286(10), 7983–7989. https://doi.org/10.1074/jbc.M110.194027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Harutyunyan, A. S., Chen, H., Lu, T., Horth, C., Nikbakht, H., Krug, B., et al. (2020). H3K27M in Gliomas Causes a One-Step Decrease in H3K27 Methylation and Reduced Spreading within the Constraints of H3K36 Methylation. Cell Reports, 33(7), 108390. https://doi.org/10.1016/j.celrep.2020.108390

    Article  CAS  PubMed  Google Scholar 

  51. Haag, D., Mack, N., Goncalves, Benites, da Silva, P., Statz, B., Clark, J., Tanabe, K., et al. (2021). H3.3–K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model. Cancer Cell, 39(3), 407-422 e13. https://doi.org/10.1016/j.ccell.2021.01.005

    Article  CAS  PubMed  Google Scholar 

  52. Silveira, A. B., Kasper, L. H., Fan, Y., Jin, H., Wu, G., Shaw, T. I., et al. (2019). H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo. Acta Neuropathologica, 137(4), 637–655. https://doi.org/10.1007/s00401-019-01975-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Furth, N., Algranati, D., Dassa, B., Beresh, O., Fedyuk, V., Morris, N., et al. (2022). H3–K27M-mutant nucleosomes interact with MLL1 to shape the glioma epigenetic landscape. Cell Reports, 39(7), 110836. https://doi.org/10.1016/j.celrep.2022.110836

    Article  CAS  PubMed  Google Scholar 

  54. Krug, B., De Jay, N., Harutyunyan, A. S., Deshmukh, S., Marchione, D. M., Guilhamon, P., et al. (2019). Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas. Cancer Cell, 35(5), 782-797 e8. https://doi.org/10.1016/j.ccell.2019.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu, M., Thomas, S. L., DeWitt, A. K., Zhou, W., Madaj, Z. B., Ohtani, H., et al. (2018). Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells. Cancer Research, 78(20), 5754–5766. https://doi.org/10.1158/0008-5472.CAN-17-3953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-Andre, V., Sigova, A. A., et al. (2013). Super-enhancers in the control of cell identity and disease. Cell, 155(4), 934–947. https://doi.org/10.1016/j.cell.2013.09.053

    Article  CAS  PubMed  Google Scholar 

  57. Nagaraja, S., Vitanza, N. A., Woo, P. J., Taylor, K. R., Liu, F., Zhang, L., et al. (2017). Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma. Cancer Cell, 31(5), 635-652 e6. https://doi.org/10.1016/j.ccell.2017.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nagaraja, S., Quezada, M. A., Gillespie, S. M., Arzt, M., Lennon, J. J., Woo, P. J., et al. (2019). Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State. Molecular Cell, 76(6), 965-980 e12. https://doi.org/10.1016/j.molcel.2019.08.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lowe, B.R., Yadav, R.K., Henry, R.A., Schreiner, P., Matsuda, A., Fernandez, A.G., et al. (2021). Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail.Elife, 10. https://doi.org/10.7554/eLife.65369

  60. Yang, S., Zheng, X., Lu, C., Li, G. M., Allis, C. D., & Li, H. (2016). Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. Genes & Development, 30(14), 1611–1616. https://doi.org/10.1101/gad.284323.116

    Article  CAS  Google Scholar 

  61. Brennan, C. W., Verhaak, R. G., McKenna, A., Campos, B., Noushmehr, H., Salama, S. R., et al. (2013). The somatic genomic landscape of glioblastoma. Cell, 155(2), 462–477. https://doi.org/10.1016/j.cell.2013.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Fontebasso, A. M., Schwartzentruber, J., Khuong-Quang, D. A., Liu, X. Y., Sturm, D., Korshunov, A., et al. (2013). Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas. Acta Neuropathologica, 125(5), 659–669. https://doi.org/10.1007/s00401-013-1095-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Jain, S.U., Khazaei, S., Marchione, D.M., Lundgren, S.M., Wang, X., Weinberg, D.N., et al. (2020). Histone H3.3 G34 mutations promote aberrant PRC2 activity and drive tumor progression. Proceedings of the National Academy of Sciences, 117(44), 27354–27364. https://doi.org/10.1073/pnas.2006076117

  64. Bressan, R. B., Southgate, B., Ferguson, K. M., Blin, C., Grant, V., Alfazema, N., et al. (2021). Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. Cell Stem Cell, 28(5), 877-893 e9. https://doi.org/10.1016/j.stem.2021.01.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fang, J., Huang, Y., Mao, G., Yang, S., Rennert, G., Gu, L., et al. (2018). Cancer-driving H3G34V/R/D mutations block H3K36 methylation and H3K36me3-MutSalpha interaction. Proceedings of the National Academy of Sciences, 115(38), 9598-9603https://doi.org/10.1073/pnas.1806355115

  66. Funato, K., Smith, R. C., Saito, Y., & Tabar, V. (2021). Dissecting the impact of regional identity and the oncogenic role of human-specific NOTCH2NL in an hESC model of H3.3G34R-mutant glioma. Cell Stem Cell, 28(5), 894-905 e7. https://doi.org/10.1016/j.stem.2021.02.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sweha, S. R., Chung, C., Natarajan, S. K., Panwalkar, P., Pun, M., Ghali, A., et al. (2021). Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas. Science Translational Medicine, 13(615), eabf7860. https://doi.org/10.1126/scitranslmed.abf7860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Voon, H. P. J., Udugama, M., Lin, W., Hii, L., Law, R. H. P., Steer, D. L., et al. (2018). Inhibition of a K9/K36 demethylase by an H3.3 point mutation found in paediatric glioblastoma. Nature Communications, 9(1), 3142. https://doi.org/10.1038/s41467-018-05607-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bjerke, L., Mackay, A., Nandhabalan, M., Burford, A., Jury, A., Popov, S., et al. (2013). Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discovery, 3(5), 512–519. https://doi.org/10.1158/2159-8290.CD-12-0426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mondal, G., Lee, J. C., Ravindranathan, A., Villanueva-Meyer, J. E., Tran, Q. T., Allen, S. J., et al. (2020). Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta Neuropathologica, 139(6), 1071–1088. https://doi.org/10.1007/s00401-020-02155-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Viaene, A. N., Santi, M., Rosenbaum, J., Li, M. M., Surrey, L. F., & Nasrallah, M. P. (2018). SETD2 mutations in primary central nervous system tumors. Acta Neuropathologica Communications, 6(1), 123. https://doi.org/10.1186/s40478-018-0623-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Louis, D. N., Perry, A., Wesseling, P., Brat, D. J., Cree, I. A., Figarella-Branger, D., et al. (2021). The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro-Oncology, 23(8), 1231–1251. https://doi.org/10.1093/neuonc/noab106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Parsons, D. W., Jones, S., Zhang, X., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). An integrated genomic analysis of human glioblastoma multiforme. Science, 321(5897), 1807–1812. https://doi.org/10.1126/science.1164382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cancer Genome Atlas Research, Brat, D. J., Verhaak, R. G., Aldape, K. D., Yung, W. K., Salama, S. R., et al. (2015). Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. New England Journal of Medicine, 372(26), 2481–98. https://doi.org/10.1056/NEJMoa1402121

    Article  CAS  Google Scholar 

  75. Pollack, I. F., Hamilton, R. L., Sobol, R. W., Nikiforova, M. N., Lyons-Weiler, M. A., LaFramboise, W. A., et al. (2011). IDH1 mutations are common in malignant gliomas arising in adolescents: A report from the Children’s Oncology Group. Childs Nervous System, 27(1), 87–94. https://doi.org/10.1007/s00381-010-1264-1

    Article  Google Scholar 

  76. Roux, A., Pallud, J., Saffroy, R., Edjlali-Goujon, M., Debily, M. A., Boddaert, N., et al. (2020). High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts. Neuro-Oncology, 22(8), 1190–1202. https://doi.org/10.1093/neuonc/noaa024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., et al. (2012). IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature, 483(7390), 479–483. https://doi.org/10.1038/nature10866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Johnson, K. C., Anderson, K. J., Courtois, E. T., Gujar, A. D., Barthel, F. P., Varn, F. S., et al. (2021). Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response. Nature Genetics, 53(10), 1456–1468. https://doi.org/10.1038/s41588-021-00926-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Capper, D., Jones, D. T. W., Sill, M., Hovestadt, V., Schrimpf, D., Sturm, D., et al. (2018). DNA methylation-based classification of central nervous system tumours. Nature, 555(7697), 469–474. https://doi.org/10.1038/nature26000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Castel, D., Philippe, C., Kergrohen, T., Sill, M., Merlevede, J., Barret, E., et al. (2018). Transcriptomic and epigenetic profiling of “diffuse midline gliomas, H3 K27M-mutant” discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location. Acta Neuropathologica Communications, 6(1), 117. https://doi.org/10.1186/s40478-018-0614-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hubner, J. M., Muller, T., Papageorgiou, D. N., Mauermann, M., Krijgsveld, J., Russell, R. B., et al. (2019). EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma. Neuro-Oncology, 21(7), 878–889. https://doi.org/10.1093/neuonc/noz058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jain, S. U., Rashoff, A. Q., Krabbenhoft, S. D., Hoelper, D., Do, T. J., Gibson, T. J., et al. (2020). H3 K27M and EZHIP Impede H3K27-Methylation Spreading by Inhibiting Allosterically Stimulated PRC2. Molecular Cell, 80(4), 726-735 e7. https://doi.org/10.1016/j.molcel.2020.09.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gessi, M., Capper, D., Sahm, F., Huang, K., von Deimling, A., Tippelt, S., et al. (2016). Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathologica, 132(4), 635–637. https://doi.org/10.1007/s00401-016-1608-3

    Article  PubMed  Google Scholar 

  84. Mariet, C., Castel, D., Grill, J., Saffroy, R., Dangouloff-Ros, V., Boddaert, N., et al. (2022). Posterior fossa ependymoma H3 K27-mutant: An integrated radiological and histomolecular tumor analysis. Acta Neuropathologica Communications, 10(1), 137. https://doi.org/10.1186/s40478-022-01442-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ryall, S., Guzman, M., Elbabaa, S. K., Luu, B., Mack, S. C., Zapotocky, M., et al. (2017). H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. Childs Nervous System, 33(7), 1047–1051. https://doi.org/10.1007/s00381-017-3481-3

    Article  Google Scholar 

  86. Sievers, P., Sill, M., Schrimpf, D., Stichel, D., Reuss, D. E., Sturm, D., et al. (2021). A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro-Oncology, 23(1), 34–43. https://doi.org/10.1093/neuonc/noaa251

    Article  CAS  PubMed  Google Scholar 

  87. Castelo-Branco, P., Choufani, S., Mack, S., Gallagher, D., Zhang, C., Lipman, T., et al. (2013). Methylation of the TERT promoter and risk stratification of childhood brain tumours: An integrative genomic and molecular study. The lancet Oncology, 14(6), 534–542. https://doi.org/10.1016/S1470-2045(13)70110-4

    Article  CAS  PubMed  Google Scholar 

  88. Dorris, K., Sobo, M., Onar-Thomas, A., Panditharatna, E., Stevenson, C. B., Gardner, S. L., et al. (2014). Prognostic significance of telomere maintenance mechanisms in pediatric high-grade gliomas. Journal of Neuro-oncology, 117(1), 67–76. https://doi.org/10.1007/s11060-014-1374-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Jafri, M. A., Ansari, S. A., Alqahtani, M. H., & Shay, J. W. (2016). Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Med, 8(1), 69. https://doi.org/10.1186/s13073-016-0324-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Killela, P.J., Reitman, Z.J., Jiao, Y., Bettegowda, C., Agrawal, N., Diaz, L.A., Jr., et al. (2013). TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proceedings of the National Academy of Sciences, 110(15), 6021-6026https://doi.org/10.1073/pnas.1303607110

  91. Karsy, M., Guan, J., Cohen, A. L., Jensen, R. L., & Colman, H. (2017). New Molecular Considerations for Glioma: IDH, ATRX, BRAF, TERT, H3 K27M. Current Neurology and Neuroscience Reports, 17(2), 19. https://doi.org/10.1007/s11910-017-0722-5

    Article  PubMed  Google Scholar 

  92. Koelsche, C., Sahm, F., Capper, D., Reuss, D., Sturm, D., Jones, D. T., et al. (2013). Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. Acta Neuropathologica, 126(6), 907–915. https://doi.org/10.1007/s00401-013-1195-5

    Article  CAS  PubMed  Google Scholar 

  93. Bryan, T. M., Englezou, A., Dalla-Pozza, L., Dunham, M. A., & Reddel, R. R. (1997). Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nature Medicine, 3(11), 1271–1274. https://doi.org/10.1038/nm1197-1271

    Article  CAS  PubMed  Google Scholar 

  94. Taylor, K. R., Mackay, A., Truffaux, N., Butterfield, Y., Morozova, O., Philippe, C., et al. (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nature Genetics, 46(5), 457–461. https://doi.org/10.1038/ng.2925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Paugh, B. S., Zhu, X., Qu, C., Endersby, R., Diaz, A. K., Zhang, J., et al. (2013). Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Research, 73(20), 6219–6229. https://doi.org/10.1158/0008-5472.CAN-13-1491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Paugh, B. S., Broniscer, A., Qu, C., Miller, C. P., Zhang, J., Tatevossian, R. G., et al. (2011). Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. Journal of Clinical Oncology, 29(30), 3999–4006. https://doi.org/10.1200/JCO.2011.35.5677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Pajovic, S., Siddaway, R., Bridge, T., Sheth, J., Rakopoulos, P., Kim, B., et al. (2020). Epigenetic activation of a RAS/MYC axis in H3.3K27M-driven cancer. Nature Communications, 11(1), 6216. https://doi.org/10.1038/s41467-020-19972-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Maxwell, H. P. (1945). The incidence of interhemispheric extension of glioblastoma multiforme through the corpus callosum. Journal of Neurosurgery, 3, 54–57.

    Article  Google Scholar 

  99. Sharifi, G., Pajavand, A. M., Nateghinia, S., Meybodi, T. E., & Hasooni, H. (2019). Glioma Migration Through the Corpus Callosum and the Brainstem Detected by Diffusion and Magnetic Resonance Imaging: Initial Findings. Frontiers in Human Neuroscience, 13, 472. https://doi.org/10.3389/fnhum.2019.00472

    Article  PubMed  Google Scholar 

  100. Claes, A., Idema, A. J., & Wesseling, P. (2007). Diffuse glioma growth: A guerilla war. Acta Neuropathologica, 114(5), 443–458. https://doi.org/10.1007/s00401-007-0293-7

    Article  PubMed  PubMed Central  Google Scholar 

  101. Buczkowicz, P., Bartels, U., Bouffet, E., Becher, O., & Hawkins, C. (2014). Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: Diagnostic and therapeutic implications. Acta Neuropathologica, 128(4), 573–581. https://doi.org/10.1007/s00401-014-1319-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Broniscer, A., & Gajjar, A. (2004). Supratentorial high-grade astrocytoma and diffuse brainstem glioma: Two challenges for the pediatric oncologist. The Oncologist, 9(2), 197–206. https://doi.org/10.1634/theoncologist.9-2-197

    Article  PubMed  Google Scholar 

  103. Arunachalam, S., Szlachta, K., Brady, S. W., Ma, X., Ju, B., Shaner, B., et al. (2022). Convergent evolution and multi-wave clonal invasion in H3 K27-altered diffuse midline gliomas treated with a PDGFR inhibitor. Acta Neuropathologica Communications, 10(1), 80. https://doi.org/10.1186/s40478-022-01381-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Hoffman, L. M., DeWire, M., Ryall, S., Buczkowicz, P., Leach, J., Miles, L., et al. (2016). Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: Implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathologica Communications, 4, 1. https://doi.org/10.1186/s40478-015-0269-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nikbakht, H., Panditharatna, E., Mikael, L. G., Li, R., Gayden, T., Osmond, M., et al. (2016). Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma. Nature Communications, 7, 11185. https://doi.org/10.1038/ncomms11185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vinci, M., Burford, A., Molinari, V., Kessler, K., Popov, S., Clarke, M., et al. (2018). Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells. Nature Medicine, 24(8), 1204–1215. https://doi.org/10.1038/s41591-018-0086-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Federico, S., Brennan, R., & Dyer, M. A. (2011). Childhood Cancer and Developmental Biology: A Crucial Partnership. Current Topics in Developmental Biology, 94, 1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Filbin, M., & Monje, M. (2019). Developmental origins and emerging therapeutic opportunities for childhood cancer (pp. 367–376). Nature Publishing Group.

    Google Scholar 

  109. Deng, Y., Bartosovic, M., Ma, S., Zhang, D., Kukanja, P., Xiao, Y., et al. (2022). Spatial profiling of chromatin accessibility in mouse and human tissues. Nature, 609(7926), 375–383. https://doi.org/10.1038/s41586-022-05094-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lu, T., Ang, C. E., & Zhuang, X. (2022). Spatially resolved epigenomic profiling of single cells in complex tissues. Cell, 185(23), 4448-4464 e17. https://doi.org/10.1016/j.cell.2022.09.035

    Article  CAS  PubMed  Google Scholar 

  111. Ziffra, R. S., Kim, C. N., Ross, J. M., Wilfert, A., Turner, T. N., Haeussler, M., et al. (2021). Single-cell epigenomics reveals mechanisms of human cortical development. Nature, 598(7879), 205–213. https://doi.org/10.1038/s41586-021-03209-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jessa, S., Blanchet-Cohen, A., Krug, B., Vladoiu, M., Coutelier, M., Faury, D., et al. (2019). Stalled developmental programs at the root of pediatric brain tumors. Nature Genetics, 51(12), 1702–1713. https://doi.org/10.1038/s41588-019-0531-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Nagaraja, S., Quezada, M. A., Gillespie, S. M., Arzt, M., Lennon, J. J., Woo, P. J., et al. (2019). Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State. Molecular Cell. https://doi.org/10.1016/j.molcel.2019.08.030

    Article  PubMed  PubMed Central  Google Scholar 

  114. Weng, Q., Wang, J., Wang, J., He, D., Cheng, Z., Zhang, F., et al. (2019). Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis. Cell Stem Cell, 24(5), 707-723 e8. https://doi.org/10.1016/j.stem.2019.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Funato, K., Major, T., Lewis, P. W., Allis, C. D., & Tabar, V. (2014). Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. Science, 346(6216), 1529–1533. https://doi.org/10.1126/science.1253799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ligon, K. L., Alberta, J. A., Kho, A. T., Weiss, J., Kwaan, M. R., Nutt, C. L., et al. (2004). The Oligodendroglial Lineage Marker OLIG2 Is Universally Expressed in Diffuse Gliomas. Journal of Neuropathology & Experimental Neurology, 63, 499.

    Article  CAS  Google Scholar 

  117. Lu, Q.R., Park, J.K., Noll, E., Chan, J.A., Alberta, J., Yuk, D., et al. (2001). Oligodendrocyte lineage genes (OLIG) as molecular markers for human glial brain tumors. Proceedings of the National Academy of Sciences, 98, 10851–10856.

  118. Tate, M. C., Lindquist, R. A., Nguyen, T., Sanai, N., Barkovich, A. J., Huang, E. J., et al. (2015). Postnatal growth of the human pons: A morphometric and immunohistochemical analysis (pp. 449–462). Wiley-Liss Inc.

    Google Scholar 

  119. Lindquist, R. A., Guinto, C. D., Rodas-Rodriguez, J. L., Fuentealba, L. C., Tate, M. C., Rowitch, D. H., et al. (2016). Identification of proliferative progenitors associated with prominent postnatal growth of the pons. Nature Communications, 7, 11628. https://doi.org/10.1038/ncomms11628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Filbin, M. G., Tirosh, I., Hovestadt, V., Shaw, M. L., Escalante, L. E., Mathewson, N. D., et al. (2018). Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq. Science, 360(6386), 331–335. https://doi.org/10.1126/science.aao4750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Jessa, S., Mohammadnia, A., Harutyunyan, A. S., Hulswit, M., Varadharajan, S., Lakkis, H., et al. (2022). K27M in canonical and noncanonical H3 variants occurs in distinct oligodendroglial cell lineages in brain midline gliomas. Nature Genetics, 54(12), 1865–1880. https://doi.org/10.1038/s41588-022-01205-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Misuraca, K. L., Barton, K. L., Chung, A., Diaz, A. K., Conway, S. J., Corcoran, D. L., et al. (2014). Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma. Acta Neuropathologica Communications, 2, 134. https://doi.org/10.1186/s40478-014-0134-6

    Article  PubMed  PubMed Central  Google Scholar 

  123. Misuraca, K. L., Hu, G., Barton, K. L., Chung, A., & Becher, O. J. (2016). A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells. Neoplasia, 18(1), 60–70. https://doi.org/10.1016/j.neo.2015.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pathania, M., De Jay, N., Maestro, N., Harutyunyan, A. S., Nitarska, J., Pahlavan, P., et al. (2017). H33(K27M) Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas. Cancer Cell, 32(5), 684-700 e9. https://doi.org/10.1016/j.ccell.2017.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Cordero, F. J., Huang, Z., Grenier, C., He, X., Hu, G., McLendon, R. E., et al. (2017). Histone H3.3K27M represses p16 to accelerate gliomagenesis in a murine model of DIPG. Molecular Cancer Research, 15, 1243–1254.

    Article  CAS  PubMed  Google Scholar 

  126. Tomita, Y., Shimazu, Y., Somasundaram, A., Tanaka, Y., Takata, N., Ishi, Y., et al. (2022). A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M. Glia, 70, 1681–1698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Mo, Y., Duan, S., Zhang, X., Hua, X., Zhou, H., Wei, H. J., et al. (2022). Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4. Cancer Discovery, 12(12), 2906–2929. https://doi.org/10.1158/2159-8290.CD-21-1492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Panditharatna, E., Marques, J. G., Wang, T., Trissal, M. C., Liu, I., Jiang, L., et al. (2022). BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma. Cancer Discovery, 12(12), 2880–2905. https://doi.org/10.1158/2159-8290.CD-21-1491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cordero, F. J., Huang, Z., Grenier, C., He, X., Hu, G., McLendon, R. E., et al. (2017). Histone H3.3K27M Represses p16 to Accelerate Gliomagenesis in a Murine Model of DIPG. Molecular Cancer Research, 15(9), 1243–1254. https://doi.org/10.1158/1541-7786.MCR-16-0389

    Article  CAS  PubMed  Google Scholar 

  130. Fortin, J., Tian, R., Zarrabi, I., Hill, G., Williams, E., Sanchez-Duffhues, G., et al. (2020). Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas. Cancer Cell, 37(3), 308-323 e12. https://doi.org/10.1016/j.ccell.2020.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chen, K.Y., Bush, K., Klein, R.H., Cervantes, V., Lewis, N., Naqvi, A., et al. (2020). Reciprocal H3.3 gene editing identifies K27M and G34R mechanisms in pediatric glioma including NOTCH signaling. Nature Research. https://doi.org/10.1038/s42003-020-1076-0

  132. He, C., Xu, K., Zhu, X., Dunphy, P. S., Gudenas, B., Lin, W., et al. (2021). Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma. Nature Communications, 12(1), 4089. https://doi.org/10.1038/s41467-021-24168-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Monje, M., Mitra, S.S., Freret, M.E., Raveh, T.B., Kim, J., Masek, M., et al. (2011). Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. Proceedings of the National Academy of Sciences, 108(11), 4453-4458https://doi.org/10.1073/pnas.1101657108

  134. Brabetz, S., Leary, S. E. S., Gröbner, S. N., Nakamoto, M. W., Seker-Cin, H., Girard, E. J., et al. (2018). A biobank of patient-derived pediatric brain tumor models. Nature Medicine, 24, 1752.

    Article  CAS  PubMed  Google Scholar 

  135. du Chatinier, A., Meel, M. H., Das, A. I., Metselaar, D. S., Waranecki, P., Bugiani, M., et al. (2022). Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma. Neuro-Oncology Advances, 4(1), vdac079. https://doi.org/10.1093/noajnl/vdac079

    Article  PubMed  PubMed Central  Google Scholar 

  136. Grasso, C. S., Tang, Y., Truffaux, N., Berlow, N. E., Liu, L., Debily, M. A., et al. (2015). Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nature Medicine, 21(7), 827. https://doi.org/10.1038/nm0715-827a

    Article  CAS  PubMed  Google Scholar 

  137. Lin, G.L., Wilson, K.M., Ceribelli, M., Stanton, B.Z., Woo, P.J., Kreimer, S., et al. (2019). Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Science Translational Medicine, 11(519). https://doi.org/10.1126/scitranslmed.aaw0064

  138. Monje, M., Cooney, T., Glod, J., Huang, J., Baxter, P., Vinitsky, A., et al. (2022). DIPG-10 A Phase I Trial Of Panobinostat Following Radiation Therapy In Children With Diffuse Intrinsic Pontine Glioma (DIPG) Or H3k27m-Mutated thalamic diffuse midline glioma (DMG): report from the pediatric brain tumor consortium (PBTC-047). Neuro-Oncology, 24, i19.

    Article  PubMed Central  Google Scholar 

  139. Anastas, J. N., Zee, B. M., Kalin, J. H., Kim, M., Guo, R., Alexandrescu, S., et al. (2019). Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG. Cancer Cell, 36(5), 528-544 e10. https://doi.org/10.1016/j.ccell.2019.09.005

    Article  CAS  PubMed  Google Scholar 

  140. Pal, S., Kozono, D., Yang, X., Fendler, W., Fitts, W., Ni, J., et al. (2018). Dual HDAC and PI3K Inhibition Abrogates NFκB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas. Cancer Research, 78(14), 4007–4021. https://doi.org/10.1158/0008-5472.CAN-17-3691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Bočkaj, I., Martini, T. E. I., De Camargo Magalhães, E. S., Bakker, P. L., Meeuwsen-De Boer, T. G. J., Armandari, I., et al. (2021). The H3.3K27M oncohistone affects replication stress outcome and provokes genomic instability in pediatric glioma. Plos Genetics, 17, e1009868.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Balakrishnan, I., Danis, E., Pierce, A., Madhavan, K., Wang, D., Dahl, N., et al. (2020). Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG. Cell Rep, 33(3), 108286. https://doi.org/10.1016/j.celrep.2020.108286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Senthil Kumar, S., Sengupta, S., Zhu, X., Mishra, D. K., Phoenix, T., Dyer, L., et al. (2020). Diffuse Intrinsic Pontine Glioma Cells Are Vulnerable to Mitotic Abnormalities Associated with BMI-1 Modulation. Molecular Cancer Research, 18(11), 1711–1723. https://doi.org/10.1158/1541-7786.MCR-20-0099

    Article  PubMed  Google Scholar 

  144. Dhar, S., Gadd, S., Patel, P., Vaynshteyn, J., Raju, G.P., Hashizume, R., et al. (2022). A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis.BioMed Central 1–14

  145. Wiese, M., Schill, F., Sturm, D., Pfister, S., Hulleman, E., Johnsen, S. A., et al. (2016). No Significant Cytotoxic Effect of the EZH2 Inhibitor Tazemetostat (EPZ-6438) on Pediatric Glioma Cells with Wildtype Histone 3 or Mutated Histone 3.3 (pp. 113–117). Georg Thieme Verlag.

    Google Scholar 

  146. Wiese, M., Hamdan, F. H., Kubiak, K., Diederichs, C., Gielen, G. H., Nussbaumer, G., et al. (2020). Combined treatment with CBP and BET inhibitors reverses inadvertent activation of detrimental super enhancer programs in DIPG cells. Springer Nature.

    Book  Google Scholar 

  147. Chung, C., Sweha, S. R., Pratt, D., Tamrazi, B., Panwalkar, P., Banda, A., et al. (2020). Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas. Cancer Cell, 38(3), 334-349 e9. https://doi.org/10.1016/j.ccell.2020.07.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Fons, N. R., Sundaram, R. K., Breuer, G. A., Peng, S., McLean, R. L., Kalathil, A. N., et al. (2019). PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. Nature Communications, 10(1), 3790–3810. https://doi.org/10.1038/s41467-019-11732-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shen, H., Yu, M., Tsoli, M., Chang, C., Joshi, S., Liu, J., et al. (2020). Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas. Neuro-Oncology, 22(1), 139–151. https://doi.org/10.1093/neuonc/noz140

    Article  CAS  PubMed  Google Scholar 

  150. Chheda, Z. S., Kohanbash, G., Okada, K., Jahan, N., Sidney, J., Pecoraro, M., et al. (2018). Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy. Journal of Experimental Medicine, 215(1), 141–157. https://doi.org/10.1084/jem.20171046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mueller, S., Taitt, J.M., Villanueva-Meyer, J.E., Bonner, E.R., Nejo, T., Lulla, R.R., et al. (2022). Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. Journal of Clinical Investigation, 132(12). https://doi.org/10.1172/JCI162283

  152. Mount, C. W., Majzner, R. G., Sundaresh, S., Arnold, E. P., Kadapakkam, M., Haile, S., et al. (2018). Potent antitumor efficacy of anti-GD2 CAR T cells in H3–K27M(+) diffuse midline gliomas. Nature Medicine, 24(5), 572–579. https://doi.org/10.1038/s41591-018-0006-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Majzner, R. G., Ramakrishna, S., Yeom, K. W., Patel, S., Chinnasamy, H., Schultz, L. M., et al. (2022). GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature, 603(7903), 934–941. https://doi.org/10.1038/s41586-022-04489-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Haydar, D., Houke, H., Chiang, J., Yi, Z., Ode, Z., Caldwell, K., et al. (2021). Cell-surface antigen profiling of pediatric brain tumors: B7–H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery. Neuro-Oncology, 23(6), 999–1011. https://doi.org/10.1093/neuonc/noaa278

    Article  CAS  PubMed  Google Scholar 

  155. Grabovska, Y., Mackay, A., O’Hare, P., Crosier, S., Finetti, M., Schwalbe, E. C., et al. (2020). Pediatric pan-central nervous system tumor analysis of immune-cell infiltration identifies correlates of antitumor immunity. Nature Communications, 11(1), 4324. https://doi.org/10.1038/s41467-020-18070-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lieberman, N. A. P., DeGolier, K., Kovar, H. M., Davis, A., Hoglund, V., Stevens, J., et al. (2019). Characterization of the immune microenvironment of diffuse intrinsic pontine glioma: Implications for development of immunotherapy. Neuro-Oncology, 21(1), 83–94. https://doi.org/10.1093/neuonc/noy145

    Article  CAS  PubMed  Google Scholar 

  157. Ross, J. L., Chen, Z., Herting, C. J., Grabovska, Y., Szulzewsky, F., Puigdelloses, M., et al. (2021). Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma. Brain, 144(1), 53–69. https://doi.org/10.1093/brain/awaa382

    Article  PubMed  Google Scholar 

  158. Keane, L., Cheray, M., Saidi, D., Kirby, C., Friess, L., Gonzalez-rodriguez, P., et al. (2021). Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas. 1–13

  159. Dolma, S., Selvadurai, H. J., Lan, X., Lee, L., Kushida, M., Voisin, V., et al. (2016). Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells. Cancer Cell, 29(6), 859–873. https://doi.org/10.1016/j.ccell.2016.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Marisetty, A. L., Lu, L., Veo, B. L., Liu, B., Coarfa, C., Kamal, M. M., et al. (2019). REST-DRD2 mechanism impacts glioblastoma stem cell-mediated tumorigenesis (pp. 775–785). Oxford University Press.

    Google Scholar 

  161. Chi, A. S., Tarapore, R. S., Hall, M. D., Shonka, N., Gardner, S., Umemura, Y., et al. (2019). Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201. Journal of Neuro-Oncology, 145(1), 97–105. https://doi.org/10.1007/s11060-019-03271-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Stein, M. N., Bertino, J. R., Kaufman, H. L., Mayer, T., Moss, R., Silk, A., et al. (2017). First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors. Clinical Cancer Research, 23(15), 4163–4169. https://doi.org/10.1158/1078-0432.CCR-16-2658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Ishizawa, J., Zarabi, S. F., Davis, R. E., Halgas, O., Nii, T., Jitkova, Y., et al. (2019). Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer Cell, 35(5), 721-737 e9. https://doi.org/10.1016/j.ccell.2019.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Graves, P. R., Aponte-Collazo, L. J., Fennell, E. M. J., Graves, A. C., Hale, A. E., Dicheva, N., et al. (2019). Mitochondrial Protease ClpP is a Target for the Anticancer Compounds ONC201 and Related Analogues. ACS Chemical Biology, 14(5), 1020–1029. https://doi.org/10.1021/acschembio.9b00222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Przystal, J. M., Cianciolo Cosentino, C., Yadavilli, S., Zhang, J., Laternser, S., Bonner, E. R., et al. (2022). Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro-Oncology, 24(9), 1438–1451. https://doi.org/10.1093/neuonc/noac041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Behjati, S., Tarpey, P. S., Presneau, N., Scheipl, S., Pillay, N., Van Loo, P., et al. (2013). Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nature Genetics, 45(12), 1479–1482. https://doi.org/10.1038/ng.2814

    Article  CAS  PubMed  Google Scholar 

  167. Papillon-Cavanagh, S., Lu, C., Gayden, T., Mikael, L. G., Bechet, D., Karamboulas, C., et al. (2017). Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nature Genetics, 49(2), 180–185. https://doi.org/10.1038/ng.3757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Snuderl, M., Dolgalev, I., Heguy, A., Walsh, M. F., Benayed, R., Jungbluth, A. A., et al. (2019). Histone H3K36I mutation in a metastatic histiocytic tumor of the skull and response to sarcoma chemotherapy. Cold Spring Harbor Molecular Case Studies, 5(5), a004606. https://doi.org/10.1101/mcs.a004606

    Article  PubMed  PubMed Central  Google Scholar 

  169. Fang, D., Gan, H., Lee, J. H., Han, J., Wang, Z., Riester, S. M., et al. (2016). The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science, 352(6291), 1344–8. https://doi.org/10.1126/science.aae0065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lu, C., Jain, S. U., Hoelper, D., Bechet, D., Molden, R. C., Ran, L., et al. (2016). Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape. Science, 352(6287), 844–849. https://doi.org/10.1126/science.aac7272

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Sloan, E. A., Cooney, T., Oberheim Bush, N. A., Buerki, R., Taylor, J., Clarke, J. L., et al. (2019). Recurrent non-canonical histone H3 mutations in spinal cord diffuse gliomas. Acta Neuropathologica, 138(5), 877–881. https://doi.org/10.1007/s00401-019-02072-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Boileau, M., Shirinian, M., Gayden, T., Harutyunyan, A. S., Chen, C. C. L., Mikael, L. G., et al. (2019). Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness. Nature Communications, 10(1), 2891. https://doi.org/10.1038/s41467-019-10705-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lehnertz, B., Zhang, Y. W., Boivin, I., Mayotte, N., Tomellini, E., Chagraoui, J., et al. (2017). H3(K27M/I) mutations promote context-dependent transformation in acute myeloid leukemia with RUNX1 alterations. Blood, 130(20), 2204–2214. https://doi.org/10.1182/blood-2017-03-774653

    Article  CAS  PubMed  Google Scholar 

  174. Bennett, R. L., Bele, A., Small, E. C., Will, C. M., Nabet, B., Oyer, J. A., et al. (2019). A Mutation in Histone H2B Represents a New Class of Oncogenic Driver. Cancer Discovery, 9(10), 1438–1451. https://doi.org/10.1158/2159-8290.CD-19-0393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Nacev, B. A., Feng, L., Bagert, J. D., Lemiesz, A. E., Gao, J., Soshnev, A. A., et al. (2019). The expanding landscape of “oncohistone” mutations in human cancers. Nature, 567(7749), 473–478. https://doi.org/10.1038/s41586-019-1038-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Bagert, J. D., Mitchener, M. M., Patriotis, A. L., Dul, B. E., Wojcik, F., Nacev, B. A., et al. (2021). Oncohistone mutations enhance chromatin remodeling and alter cell fates. Nature Chemical Biology, 17(4), 403–411. https://doi.org/10.1038/s41589-021-00738-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Feinberg, A. P., & Vogelstein, B. (1983). Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature, 301(5895), 89–92. https://doi.org/10.1038/301089a0

    Article  CAS  PubMed  Google Scholar 

  178. Hanahan, D. (2022). Hallmarks of Cancer: New Dimensions. Cancer Discovery, 12(1), 31–46. https://doi.org/10.1158/2159-8290.CD-21-1059

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors acknowledge support from the National Cancer Institute (CA096832 to SJB, CA265285 to KB, and CA271570 to JTR) and the American Lebanese Associated Charities. We thank members of the Baker lab and Dr. David Ellison for helpful discussions.

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  1. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Jennifer K. Ocasio, Kaitlin M. Budd, Jordan T. Roach, Jared M. Andrews & Suzanne J. Baker

  2. St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA

    Kaitlin M. Budd, Jordan T. Roach & Suzanne J. Baker

  3. College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, USA

    Jordan T. Roach

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Ocasio, J.K., Budd, K.M., Roach, J.T. et al. Oncohistones and disrupted development in pediatric-type diffuse high-grade glioma. Cancer Metastasis Rev 42, 367–388 (2023). https://doi.org/10.1007/s10555-023-10105-2

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