We've put together a quick overview of the most common histone mutations affecting histone 3 (H3) - H3K27M, H3K36M, H3G34 (W/V/R) - so you can easily find the right tools to study your histone mutant.

Histone mutations in cancer​

Histone H3 mutations have emerged as pivotal drivers in the development of diffuse midline gliomas (DMG), a devastating group of brain tumors that arise within the central nervous system (CNS). These tumors, which include diffuse intrinsic pontine gliomas (DIPG) and other midline gliomas, are most commonly found in midline structures such as the brainstem, thalamus, and spinal cord. Among these, the H3K27M mutation, a substitution of lysine with methionine at position 27 of histone H3, has been identified as a hallmark genetic alteration, particularly in pediatric brain tumors.

Recurrent histone mutations have been recently described in various cancer types, including brain tumors, chondroblastoma, giant cell tumors of bone, and leukemia. These aggressive tumors are part of a broader category known as brain neoplasms. Current research suggests that histone mutations alter the epigenetic landscape, but underlying mechanisms are not completely understood. Genetic alterations, including mutations in H3, contribute to tumor heterogeneity and are key to tumor classification.

The identification of widespread recurrent driver mutations in histones has raised significant interest in the development of novel targeted epigenetic therapies for histone mutant tumors, as well as biomarkers for diagnostics and monitoring of drug response. Among these, diffuse midline glioma and h3k27m mutant glioma are clinically significant entities, particularly in pediatric patients. Pediatric high-grade gliomas, characterized by unique molecular features, often harbor H3K27M mutations. Advances in molecular diagnostics have highlighted the importance of molecular features in tumor classification and therapy selection. Tumor location, such as the brainstem, thalamus, or spinal cord, plays a crucial role in prognosis and treatment planning. The aggressive nature of these tumors leads to rapid tumor progression, which significantly impacts patient outcomes. Tumor growth remains a major challenge, emphasizing the need for therapies that can inhibit or slow this process. The extent of tumor resection can also influence outcomes, although complete resection is often not feasible due to tumor location. The H3K27M mutation is recognized as an independent prognostic factor for survival, and median overall survival is a key clinical endpoint in evaluating treatment efficacy for these patients.

Here we review the five common histone mutations affecting H3 - H3K27M, H3K36M, and H3G34 (W/V/R) - and recommend our best recombinant monoclonal antibodies to study these targets.

H3K27M

H3K27M mutations are found in pediatric brain tumors and adult cancers, such as acute myeloid leukemia, melanoma, and glioma1. The H3 K27M mutant represents a key molecular subtype in diffuse midline gliomas, with the H3.3 K27M variant being particularly significant. H3K27M acts as a suppressor of the PCR2 complex, leading to a global reduction of H3K27 di- and trimethylation levels (H3K27me2 and H3K27me3)2. This histone mutation has significant epigenetic consequences, altering chromatin structure and gene expression. In addition, associated genetic alterations often co-occur with H3K27M, further influencing tumor classification and prognosis. The suppression of methylation is also influenced by chromatin remodelling genes, which play a crucial role in the epigenetic deregulation observed in these tumors.

Figure 1. Immunocytochemistry/ Immunofluorescence - Anti-Histone H3 (mutated K27M) antibody [EPR18340] - ChIP Grade (ab190631).

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H3K36M

H3K36M is a potential oncogenic driver mutation in chondroblastomas; also found in pediatric soft tissue sarcomas, HNSCC, and in other tumor types such as diffuse hemispheric glioma, which is associated with specific histone mutations. Similar to H3K27M, the H3K36M mutation suppresses the methyltransferase activity of SETD2 and NSD family proteins and leads to the global reduction of H3K36 di- and trimethylation levels. H3K36M mutations have also been identified in high-grade glioma and pediatric high-grade glioma, highlighting their relevance in the molecular classification and prognosis of these aggressive tumors.

Figure 2. Flow Cytometry (Intracellular) - Anti-Histone H3 (mutated K36M) antibody [EPR23614-91] (ab256384).

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H3G34W

H3G34W mutation is a substitution of glycine 34 with tryptophan (G34W); it’s a high-frequency mutation (>90%) in giant cell tumor of bone (GCTB).

It is important to distinguish GCTB from glioneuronal tumor and glioneuronal tumors, as these entities have different molecular features, genetic alterations, and methylation profiles that are critical for accurate diagnosis and classification.

In GCTB, H3.3G34W expression was shown to promote cellular proliferation in vitro by inducing transcriptional deregulation and splicing alterations.

Figure 3. Western blot - Anti-Histone H3.3 (mutated G34W) antibody [EPR23581-39] - ChIP Grade (ab272691).

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H3G34V

H3G34V mutation is a substitution of glycine 34 with valine (G34V). H3G34V/R mutations are predominantly found in high-grade gliomas of children and adolescents. They are associated with genetic alterations, specifically loss-of-function mutations in p53 and ATRX, as well as other associated genetic alterations, and with the deregulated expression of N-Myc protein. These tumors often involve chromatin remodeling genes, which play a critical role in chromatin deregulation and impact tumor behavior and classification.

Figure 4. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-Histone H3.3 (mutated G34V) antibody [EPR23520-5] - ChIP Grade (ab254401).

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H3G34R

H34G34R mutation is a substitution of glycine 34 with arginine (G34R).

H3G34V/R mutations are predominantly found in high-grade gliomas and are associated with loss-of-function mutations in   p53   and  ATRX1, which can impact tumor cells by altering cell differentiation pathways. These mutations may disrupt normal neuronal differentiation, contributing to the abnormal development and aggressive behavior of high-grade gliomas.

Figure 5. Immunohistochemistry (Formalin/PFA-fixed paraffin-embedded sections) - Anti-Histone H3.3 (mutated G34R) antibody [EPR23519-91] - ChIP Grade (ab254402).

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References

1. Lowe, B. R., Maxham, L. A., Hamey, J. J.  et al.  Histone H3 mutations: an updated view of their role in chromatin deregulation and cancer.  Cancers  11, 660 (2019).
2. Lewis, P. W.  et al.  Inhibition of PRC2 activity by a gain of function H3 mutation found in pediatric glioblastoma.  Science  340, 857–861 (2013).
3. Funato, K. & Tabar, V. Histone mutations in cancer.  Annu. Rev. Cancer Biol.  2, 337–351 (2018).
4. Lim, J.  et al.  The histone variant H3.3 G34W substitution in giant cell tumor of the bone links chromatin and RNA processing.  Sci. Rep.  7, 13459 (2019).
5. Bjerke, L.  et al.  Histone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN.  Cancer Discov.  3, 512–519 (2013).