{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T16:16:28Z","timestamp":1791994588410,"version":"4.4.0"},"reference-count":83,"publisher":"American Association for Cancer Research (AACR)","issue":"6","funder":[{"name":"National Cancer Institute","award":["R01CA227640"],"award-info":[{"award-number":["R01CA227640"]}]},{"DOI":"10.13039\/100011034","name":"Sidney Kimmel Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100011034","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100019937","name":"William Guy Forbeck Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019937","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Wong Family"},{"DOI":"10.13039\/100007886","name":"Dana-Farber Cancer Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007886","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,6,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in a wide range of cancers, including acute myeloid leukemia (AML) and glioma. Mutant IDH enzymes convert 2-oxoglutarate (2OG) to (R)-2-hydroxyglutarate [(R)-2HG], an oncometabolite that is hypothesized to promote cellular transformation by dysregulating 2OG-dependent enzymes. The only (R)-2HG target that has been convincingly shown to contribute to transformation by mutant IDH is the myeloid tumor suppressor TET2. However, there is ample evidence to suggest that (R)-2HG has other functionally relevant targets in IDH-mutant cancers. Here, we show that (R)-2HG inhibits KDM5 histone lysine demethylases and that this inhibition contributes to cellular transformation in IDH-mutant AML and IDH-mutant glioma. These studies provide the first evidence of a functional link between dysregulation of histone lysine methylation and transformation in IDH-mutant cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Mutant IDH is known to induce histone hypermethylation. However, it is not known if this hypermethylation is functionally significant or is a bystander effect of (R)-2HG accumulation in IDH-mutant cells. Here, we provide evidence that KDM5 inhibition by (R)-2HG contributes to mutant IDH\u2013mediated transformation in AML and glioma.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 1275<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-0825","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T09:01:26Z","timestamp":1677488486000},"page":"1478-1497","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["<i>(R)<\/i>\n                    -2-Hydroxyglutarate Inhibits KDM5 Histone Lysine Demethylases to Drive Transformation in\n                    <i>IDH<\/i>\n                    -Mutant Cancers"],"prefix":"10.1158","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1515-7898","authenticated-orcid":false,"given":"Kathryn","family":"Gunn","sequence":"first","affiliation":[{"name":"1Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6641-5856","authenticated-orcid":false,"given":"Matti","family":"Myllykoski","sequence":"additional","affiliation":[{"name":"2Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland; Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7561-235X","authenticated-orcid":false,"given":"John Z.","family":"Cao","sequence":"additional","affiliation":[{"name":"3Committee on Cancer Biology, Biological Sciences Division, University of Chicago, Chicago, Illinois."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4555-988X","authenticated-orcid":false,"given":"Manna","family":"Ahmed","sequence":"additional","affiliation":[{"name":"4Cancer Signaling and Epigenetics Program, Cancer Epigenetic Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5855-2180","authenticated-orcid":false,"given":"Bofu","family":"Huang","sequence":"additional","affiliation":[{"name":"1Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5377-4187","authenticated-orcid":false,"given":"Betty","family":"Rouaisnel","sequence":"additional","affiliation":[{"name":"1Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9248-7351","authenticated-orcid":false,"given":"Bill H.","family":"Diplas","sequence":"additional","affiliation":[{"name":"5Department of Pathology, Duke University Medical Center, Durham, North Carolina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8359-1760","authenticated-orcid":false,"given":"Michael M.","family":"Levitt","sequence":"additional","affiliation":[{"name":"6Children's Medical Center Research Institute and Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, Texas."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1626-1363","authenticated-orcid":false,"given":"Ryan","family":"Looper","sequence":"additional","affiliation":[{"name":"7Department of Chemistry, University of Utah, Salt Lake City, Utah."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3707-9889","authenticated-orcid":false,"given":"John G.","family":"Doench","sequence":"additional","affiliation":[{"name":"8Broad Institute of MIT and Harvard, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7733-600X","authenticated-orcid":false,"given":"Keith L.","family":"Ligon","sequence":"additional","affiliation":[{"name":"8Broad Institute of MIT and Harvard, Cambridge, Massachusetts."},{"name":"9Department of Pathology, Boston Children's Hospital and Brigham and Women's Hospital, Boston, Massachusetts."},{"name":"10Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3779-4540","authenticated-orcid":false,"given":"Harley 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