{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:43Z","timestamp":1792790383361,"version":"4.5.0"},"posted":{"date-parts":[[2026,6,18]]},"group-title":"Cancer Biology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["1R01NS13151501"],"award-info":[{"award-number":["1R01NS13151501"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Rogel Cancer Center Discovery Grant"],"award-info":[{"award-number":["Rogel Cancer Center Discovery Grant"]}],"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Michigan","award":["Radiology SEED"],"award-info":[{"award-number":["Radiology SEED"]}],"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Diffuse midline glioma (DMG) is a lethal pediatric brain tumor driven by the H3K27M oncohistone, which disrupts epigenetic regulation and promotes tumor proliferation. While prior studies show that H3K27M is essential for tumor initiation, its role in established tumors, tumor microenvironment (TME) regulation, and therapeutic response remain unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Here, we developed inducible and reversible H3.3K27M and H3.1K27M cell and mouse models to study oncohistone-dependent effects and the immune\/stromal microenvironment. We generated a tetracycline-inducible PiggyBac-based oncohistone expression cassette in patient- and murine-derived models and validated inducible and reversible H3K27M expression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Re-expression of H3K27M in knockout cells induced morphological changes and suppressed astrocytic markers. Chromatin accessibility profiling revealed locus-specific differences between ON, OFF, and OFF\u2013ON, including changes at loci associated with immune regulation and tumor\u2013microenvironment interactions. Single-cell RNA sequencing demonstrated that the oncohistone reshapes the TME. H3K27M expression promotes tumor\u2013neuron interactions, enhances neuronal excitability, excitatory\/inhibitory imbalance, and synaptic connectivity that likely supports tumor proliferation. These effects are associated with increased glutamatergic signaling and enhanced tumor\u2013neuron coupling through glutamate transport and receptor pathways, including EAAT1 (\n                    <jats:italic>SLC1A3<\/jats:italic>\n                    ) and AMPARs (\n                    <jats:italic>GRIA3<\/jats:italic>\n                    ). Conversely, H3K27M inhibition reduces neuronal excitation, disrupts tumor-associated signaling, and partially restores neuron\u2013neuron and neuron\u2013immune communications. These findings identify H3K27M as a key driver of excitatory neuron-to-tumor coupling and immunosuppression in DMG.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Overall, our findings demonstrate that H3K27M extensively reshapes TME in DMG and support direct oncohistone targeting as a potential therapeutic strategy, including potential CRISPR-based or small-molecule approaches for patients with H3K27M-mutant DMG.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>We developed inducible and reversible H3K27M DMG models to investigate the role of H3K27M in the tumor microenvironment.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>H3K27M promotes tumor\u2013neuron communication, while its inhibition disrupts these interactions, supporting H3K27M-targeted therapies for DMG.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Importance of Study<\/jats:title>\n                  <jats:p>Diffuse midline glioma (DMG) remains one of the deadliest pediatric brain tumors, with limited effective treatment options and poor patient survival. Although the H3K27M oncohistone is recognized as a key driver of tumor initiation, its role in maintaining tumor progression and shaping the tumor microenvironment is unclear. In this study, we developed inducible and reversible H3.3K27M and H3.1K27M murine and patient-derived DMG cell- and mouse-models that enabled precise control of the oncohistone expression. Using these models, we demonstrate that H3K27M actively promotes tumor\u2013neuron interactions, neuronal excitability, and glutamatergic signaling pathways that support tumor growth. Importantly, inhibition of H3K27M disrupted these tumor-associated signaling networks and partially restored neuron\u2013 immune communication within the tumor microenvironment. Together, these findings demonstrate that H3K27M extensively reshapes the tumor microenvironment in these Diffuse Midline Gliomas and provides strong rationale for directly targeting the oncohistone as a therapeutic strategy for patients with H3K27M-mutant DMG.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.17.731637","type":"posted-content","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T13:25:11Z","timestamp":1781789111000},"source":"Crossref","is-referenced-by-count":0,"title":["Oncohistone inhibition reshapes tumor\u2013microenvironment communication in Diffuse Midline Glioma (DMG)"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0895-9913","authenticated-orcid":false,"given":"Niloofar","family":"Khairkhah","sequence":"first","affiliation":[{"name":"Department of Radiology, The University of Michigan Medical School, Ann Arbor, MI 48109, United States"},{"name":"Center for Molecular Imaging, The University of Michigan Medical School, Ann Arbor, MI 48109, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa M. 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