1. Glioma, Chondroblastoma and Giant Cell Tumour of Bone Share Mutations
Normal
The development of some gliomas as well as some bone cancers have been seen at a higher prevalence in children than in adults. Some of these cancers have been shown to have low survival rates and difficult treatments. These cancers also have been shown to have shared mutations in high levels in a polymorphism to Histone H3. Pediatric gliomas have been shown to have these mutations in 70-80% of cancers, chondroblastoma has been shown to have the same mutations in 95% of samples, and giant cell tumor of bone shares it in 92% of cancers. *Note: Chondroblastoma and giant cell tumor of bone have mutations in different H3.3 genes (A and B), but the two proteins are identical, with differences in untranslated mRNA sequences and regulatory sequences.*
Fitzgerald et al., 2014
Puri and Agarwal, 2007
Holland, 2001

2. Specific Histone H3.3 Mutations are Correlated with Cancer
Looking at the actual mutations in these cancers, they found that most mutations in these cancers are shared, specifically 27 Lysine changes to Methionine in pediatric cancers. Both of these mutations are seen in the N-terminal tail of the Histone. The N-terminal tail in these proteins is typically involved in epigenetic control of these proteins, and has been connected to genome integrity during chromosome segregation.
Yuen and Knoepfler, 2013
Szenker et al., 2011

3. Disruption of Histone H3.3 leads to Developmental Disruption
In order to better understand the activity of this protein, several knockout studies were done, yielding vastly different results across organisms. Even with these different results, they mostly affected development of the organism. In Drosophila, knocking out one of the H3.3 genes has little effect, but knocking out both leads to reduced viability and sterility. Xenopus laevis knockouts lead to defects in late gastrulation, and zebrafish disruption alters neural crest development. Mammal studies have only knocked out one gene at a time in mice, but either gene being disrupted leads to neonatal lethality and developmental defects.
Cox et al., 2012

4. H3.3 Methylation Impacts Transcription by Suppressing DNA Polymerase and Promoting Intron Removal
More recent studies have shown that the mechanism of H3.3 transcriptional control acts in two ways. Both mechanisms feature methylated H3.3 binding to BS69 and other proteins in a complex. This protein complex suppresses DNA polymerase and promotes removal of introns, allowing two distinct pathways of mRNA control. Mutations to transcriptional control are common in many types of cancer, so therefore it can be expected that mutations to H3.3 that limit it’s ability to be methylated could lead to tumor formation.
Lan and Shi, 2014

5. Mutation of H3.3 Prevents Methylation and Leads to Overactivity
Many mutations of H3.3 that lead to cancer are in the N-terminal tail, and limit the methylation. The mutation of K27 to M prevents methylation and controls transcriptional inhibition via PRC2 complex. This specific mutation leads to overexpression of genes through two mechanisms: sequestration of the PRC2 complex, or binding of the complex to the DNA, which therefore inhibits the binding of other complexes. Because of this mutation, and other similar ones, overexpression of specific proteins can occur, as well as a higher susceptibility to genome damage.
Yuen and Knoepfler, 2013

6. Various Cancer Keystone Proteins are Affected
p16INK4A
Myc
p53
Mutations in many proteins are correlated with mutations in H3.3, and some are directly overexpressed due to failures in regulation in H3.3. p53 is mutated in 60% of cancers with mutations in H3.3. Some proteins are actually more methylated in cancers with H3.3 mutations, although the mechanisms of this pathway is poorly understood (p16). Many oncogenes, such as Myc, are also overexpressed due to the lack of methylation on the histones.
Li et al., 2011
Malecka et al., 2009
Tansey, 2014

7. Current Understanding Limits Direct Treatment, but Indirect Treatment can be Used
Histone and epigenetic regulation is incredibly important for the life of the cell and control, so it is difficult to influence this system without mistakenly inactivating genes. Limits on our understanding also prevents more specific attacks on the pathway. Many of the downstream targets have been used, though. Chemotherapeutic agents that target Myc have been used in cancers with mutations in Histone H3.3 such as astrocytomas, gliomas, chondroblastoma, and giant cell tumor of bone.
Huang et al., 2014

8. References
Holland EC. Gliomagenesis: Genetic Alterations and Mouse Models. Nature. 2001; 2:
Fitzgerald J, Broehm C, Chafey D, Treme G. Chondroblastoma of the Knee Treated with Resection and Osteochondral Allograft Reconstruction. Case Rep Orthop. 2014; 1-7.
Puri A, Agarwal M. Treatment of Giant Cell Tumor of Bone: Current Concepts. Indian J Orthop. 2007; 41(2):
Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, Wedge DC, Cooke SL, Gundem G, Davies H, et al. Distinct H3F3A and H3F3B Driver Variants Define Chondroblastoma and Giant Cell Tumour of Bone. Nat Genet. 2013; 45(12): 1-12.
Szenker E, Ray-Gallet D, Almouzni G. The Double Face of the Histone Variant H3.3. Cell Res. 2011; 21:
Cox SG, Kim H, Garnett AT, Medeiros DM, An W, Crump JG. An Essential Role of the Variant Histone H3.3 for Ectomesenchyme Potential of the Cranial Neural Crest. PLOS Gen. 2012; 8(9): 1-17.
Lan F, Shi Y. Histone H3.3 and Cancer: A Potential Reader Connection. PNAS. 2015; 112(22):
Yuen BTK, Knoepfler PS. Histone H3.3 Mutations: A Variant Path to Cancer. Cancer Cell. 2013; 24(5): 1-15.
Malecka KA, Ho WC, Marmorstein R. Crystal Structure of a p53 Core Tetramer Bound to DNA. Oncogene. 2009; 28(3):
Li J, Poi MJ, Tsai MD. The Regulatory Mechanisms of Tumor Suppressor P16INK4A and Relevance to Cancer. Biochemistry. 2011; 50(25):
Tansey, WP. Mammalian MYC Proteins and Cancer. New Jour Science. 2014; 1-27.
Bjerke L, Mackay A, Nandhabalan M, Burford A, Jury A, Popov S, Bax DA, Carvalho D, Taylor KR, Vinci M, et al. Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN. Cancer Discov. 2013; 3(5):
Huang H, Weng H, Zhou H, Qu L. Attacking c-Myc: Targeted and Combined Therapies for Cancer. Curr Pharm Des. 2014; 20(42):