{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T01:50:39Z","timestamp":1775785839171,"version":"3.50.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LQ24H200001"],"award-info":[{"award-number":["LQ24H200001"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Multiple myeloma (MM) is an incurable plasma cell malignancy with high heterogeneity. Current staging systems, including the International Staging System (ISS) and Revised ISS (R-ISS), have limited prognostic accuracy. Given the role of histone modifications in MM progression, we developed a histone modification-related (HMR) prognostic model to improve MM risk stratification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Gene expression and mutation data were downloaded from the Gene Expression Omnibus database and the Cancer Genome Atlas. Prognostic HMR-related genes were identified through a combination of univariate Cox regression, least absolute shrinkage and selection operator Cox regression, and random survival forest analysis. The genes identified were then used to construct the HMR risk score model using multivariate Cox regression. The model was validated using Kaplan-Meier survival, time-dependent receiver operating characteristic curves analysis. A nomogram combining the HMR score with clinical features was developed. Functional enrichment, immune infiltration, somatic mutation, and drug sensitivity analysis were conducted to explore the biological relevance of the model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Seven HMR genes with prognostic significance were identified. The HMR risk score stratified patients into high-risk and low-risk groups, with significant survival differences. The model demonstrated favorable predictive performance, and was shown to be an independent prognostic factor. The nomogram showed good calibration and discriminative ability, offering a practical tool for individual patient risk assessment. Functional analysis revealed that the HMR risk score is associated with dysregulated cell cycle progression, proliferation, and immunosuppression in MM, which may contribute to disease progression and drug resistance. Moreover, drug sensitivity analysis indicated potential associations between the HMR score and response to specific therapeutic agents, highlighting its potential role in guiding personalized treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We developed an HMR gene signature that has potential for prognostic prediction and may help guide personalized treatment strategies in MM.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1613631","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T04:10:45Z","timestamp":1756354245000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification and validation of a histone modification-related gene signature to predict the prognosis of multiple myeloma"],"prefix":"10.3389","volume":"16","author":[{"given":"Juan","family":"Lyu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanmei","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Qian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1126\/science.aal2512","article-title":"PCGF3\/5-PRC1 initiates polycomb recruitment in X chromosome inactivation","volume":"356","author":"Almeida","year":"2017","journal-title":"Science."},{"key":"B2","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.semcancer.2017.09.007","article-title":"Epigenetics in multiple myeloma: from mechanisms to therapy","volume":"51","author":"Alzrigat","year":"2018","journal-title":"Seminars Cancer Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1056\/NEJMoa1611750","article-title":"Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma","volume":"376","author":"Attal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e70080","DOI":"10.1002\/mco2.70080","article-title":"Epigenetic modifications in early stage lung cancer: pathogenesis, biomarkers, and early diagnosis","volume":"6","author":"Bi","year":"","journal-title":"MedComm"},{"key":"B5","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.molcel.2012.11.006","article-title":"Histone lysine methylation dynamics: establishment, regulation, and biological impact","volume":"48","author":"Black","year":"2012","journal-title":"Mol. Cell."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1323","DOI":"10.1182\/blood.2019000015","article-title":"Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia","volume":"134","author":"Broux","year":"2019","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1554","DOI":"10.1016\/j.apsb.2023.01.020","article-title":"Pancreatic melatonin enhances anti-tumor immunity in pancreatic adenocarcinoma through regulating tumor-associated neutrophils infiltration and NETosis","volume":"13","author":"Chan","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2613","DOI":"10.1158\/1078-0432.CCR-10-2156","article-title":"Aberrations of EZH2 in cancer","volume":"17","author":"Chase","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/s41576-024-00761-7","article-title":"Chromosomal instability as a driver of cancer progression","volume":"26","author":"Chen","year":"2025","journal-title":"Nat. Rev. Genet."},{"key":"B10","first-page":"589","article-title":"Histone modifications and cancer: biomarkers of prognosis?","volume":"2","author":"Chervona","year":"2012","journal-title":"Am. J. Cancer Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1186\/s12885-018-4066-6","article-title":"Prognostic implications of polycomb proteins ezH2, suz12, and eed1 and histone modification by H3K27me3 in sarcoma","volume":"18","author":"Cho","year":"2018","journal-title":"BMC Cancer"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e1003323","DOI":"10.1371\/journal.pmed.1003323","article-title":"Bone marrow microenvironments that contribute to patient outcomes in newly diagnosed multiple myeloma: a cohort study of patients in the total therapy clinical trials","volume":"17","author":"Danziger","year":"2020","journal-title":"PLoS Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"R47","DOI":"10.1186\/gb-2014-15-3-r47","article-title":"Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines","volume":"15","author":"Geeleher","year":"","journal-title":"Genome Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e107468","DOI":"10.1371\/journal.pone.0107468","article-title":"pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels","volume":"9","author":"Geeleher","year":"","journal-title":"PLoS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s12291-023-01152-1","article-title":"Documentation of international staging system (ISS) and revised international staging system (R-ISS) for multiple myeloma at a tertiary care center: a clinical audit","volume":"40","author":"Girija Sivasankaran","year":"2025","journal-title":"Ind. J. Clin. Biochem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/s41588-018-0114-z","article-title":"UTX-Mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs","volume":"50","author":"Gozdecka","year":"2018","journal-title":"Nat. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41408-022-00679-5","article-title":"High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions","volume":"12","author":"Hagen","year":"2022","journal-title":"Blood Cancer J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1007\/s13577-022-00707-3","article-title":"KAT2A affects tumor metabolic reprogramming in Colon cancer progression through epigenetic activation of E2F1","volume":"35","author":"Han","year":"2022","journal-title":"Hum. Cell."},{"key":"B19","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1158\/1535-7163.MCT-15-0486","article-title":"EZH2 inhibition blocks multiple myeloma cell growth through upregulation of epithelial tumor suppressor genes","volume":"15","author":"Hernando","year":"2016","journal-title":"Mol. Cancer Ther."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2767","DOI":"10.3390\/biomedicines10112767","article-title":"The role of epigenetics in the development and progression of multiple myeloma","volume":"10","author":"Ismail","year":"2022","journal-title":"Biomedicines"},{"key":"B21","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12943-025-02255-4","article-title":"The epigenetic hallmarks of immune cells in cancer","volume":"24","author":"Ji","year":"2025","journal-title":"Mol. Cancer"},{"key":"B22","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1186\/s12943-022-01605-w","article-title":"MARCKSL1-2 reverses docetaxel-resistance of lung adenocarcinoma cells by recruiting SUZ12 to suppress HDAC1 and elevate miR-200b","volume":"21","author":"Jiang","year":"","journal-title":"Mol. Cancer"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e744","DOI":"10.1002\/ctm2.744","article-title":"Posttranslational modification of Aurora a-NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma","volume":"12","author":"Jiang","year":"","journal-title":"Clin. Transl. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"665","DOI":"10.3389\/fonc.2018.00665","article-title":"Deregulation and targeting of TP53 pathway in multiple myeloma","volume":"8","author":"Jovanovi\u0107","year":"2018","journal-title":"Front. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s11864-025-01295-8","article-title":"Impact of genetic polymorphisms on treatment outcomes of proteasome inhibitors and immunomodulatory drugs in multiple myeloma","volume":"26","author":"Karimi","year":"2025","journal-title":"Curr. Treat. Options Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2007.02.005","article-title":"Chromatin modifications and their function","volume":"128","author":"Kouzarides","year":"2007","journal-title":"Cell."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2962","DOI":"10.1182\/blood-2007-10-078022","article-title":"Multiple myeloma","volume":"111","author":"Kyle","year":"2008","journal-title":"Blood"},{"key":"B28","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.semcancer.2021.03.025","article-title":"Cancer epigenetics: past, present and future","volume":"83","author":"Lee","year":"2022","journal-title":"Seminars Cancer Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/j.cell.2007.01.015","article-title":"The role of chromatin during transcription","volume":"128","author":"Li","year":"2007","journal-title":"Cell."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1002\/ijc.35057","article-title":"Identifying high-risk multiple myeloma patients: a novel approach using a clonal gene signature","volume":"155","author":"Li","year":"2024","journal-title":"Int. J. Cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1038\/s41419-021-04077-w","article-title":"KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer","volume":"12","author":"Lu","year":"2021","journal-title":"Cell. Death Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"5781","DOI":"10.1158\/0008-5472.CAN-05-4186","article-title":"The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance","volume":"66","author":"Maiso","year":"2006","journal-title":"Cancer Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1038\/nature09784","article-title":"The polycomb complex PRC2 and its mark in life","volume":"469","author":"Margueron","year":"2011","journal-title":"Nature"},{"key":"B34","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1182\/blood-2010-07-298349","article-title":"The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells","volume":"117","author":"Martinez-Garcia","year":"2011","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1007\/s00335-009-9218-1","article-title":"Emerging similarities in epigenetic gene silencing by long noncoding RNAs","volume":"20","author":"Nagano","year":"2009","journal-title":"Mamm. Genome"},{"key":"B36","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/s41419-021-03447-8","article-title":"A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma","volume":"12","author":"Nylund","year":"2021","journal-title":"Cell. Death Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"6212","DOI":"10.1038\/s41388-018-0393-y","article-title":"Methylation of aurora kinase a by MMSET reduces p53 stability and regulates cell proliferation and apoptosis","volume":"37","author":"Park","year":"2018","journal-title":"Oncogene"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e549","DOI":"10.1038\/bcj.2017.27","article-title":"Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control","volume":"7","author":"Pawlyn","year":"2017","journal-title":"Blood Cancer J."},{"key":"B39","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s40164-024-00507-5","article-title":"Exploring the role of histone deacetylase and histone deacetylase inhibitors in the context of multiple myeloma: mechanisms, therapeutic implications, and future perspectives","volume":"13","author":"Pu","year":"2024","journal-title":"Exp. Hematol. Oncol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3259","DOI":"10.1158\/1078-0432.CCR-10-3012","article-title":"Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide","volume":"17","author":"Santo","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/carcin\/bgp220","article-title":"Epigenetics in cancer","volume":"31","author":"Sharma","year":"2010","journal-title":"Carcinogenesis"},{"key":"B42","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/s41586-021-03903-7","article-title":"UTX condensation underlies its tumour-suppressive activity","volume":"597","author":"Shi","year":"2021","journal-title":"Nat. 2021 Sept."},{"key":"B43","doi-asserted-by":"publisher","first-page":"20004","DOI":"10.1073\/pnas.2005052117","article-title":"Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma","volume":"117","author":"Shirazi","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B44","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1007\/s11427-023-2604-8","article-title":"TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation","volume":"67","author":"Sun","year":"2024","journal-title":"Sci. China Life Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/S0140-6736(21)00135-5","article-title":"Multiple myeloma","volume":"397","author":"van de Donk","year":"2021","journal-title":"Lancet"},{"key":"B47","doi-asserted-by":"publisher","first-page":"31820","DOI":"10.18632\/oncotarget.25806","article-title":"Development of novel SUV39H2 inhibitors that exhibit growth suppressive effects in mouse xenograft models and regulate the phosphorylation of H2AX","volume":"9","author":"Vougiouklakis","year":"2018","journal-title":"Oncotarget"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3911","DOI":"10.1200\/JCO.2014.59.1503","article-title":"Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma","volume":"33","author":"Walker","year":"2015","journal-title":"JCO"},{"key":"B49","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1186\/s12935-019-0982-z","article-title":"Histone methyltransferase SUV39H2 regulates cell growth and chemosensitivity in glioma via regulation of hedgehog signaling","volume":"19","author":"Wang","year":"2019","journal-title":"Cancer Cell. Int."},{"key":"B50","doi-asserted-by":"publisher","first-page":"122916","DOI":"10.1016\/j.lfs.2024.122916","article-title":"BUB1 potentiates gastric cancer proliferation and metastasis by activating TRAF6\/NF-\u03baB\/FGF18 through m6A modification","volume":"353","author":"Wang","year":"2024","journal-title":"Life Sci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1038\/leu.2015.169","article-title":"MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib","volume":"29","author":"Xie","year":"2015","journal-title":"Leukemia"},{"key":"B52","doi-asserted-by":"publisher","first-page":"13036","DOI":"10.1111\/jcmm.15901","article-title":"Inhibition of BRD4 triggers cellular senescence through suppressing aurora kinases in oesophageal cancer cells","volume":"24","author":"Xu","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1038\/s41467-018-03781-0","article-title":"PCGF5 is required for neural differentiation of embryonic stem cells","volume":"9","author":"Yao","year":"2018","journal-title":"Nat. Commun."},{"key":"B54","doi-asserted-by":"publisher","first-page":"4974","DOI":"10.1002\/tox.24370","article-title":"Histone methyltransferase SUV39H2 supports nasopharyngeal carcinoma cell metastasis by regulation of SIRT1","volume":"39","author":"You","year":"2024","journal-title":"Environ. Toxicol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1186\/s13148-018-0562-4","article-title":"Identification of SUV39H2 as a potential oncogene in lung adenocarcinoma","volume":"10","author":"Zheng","year":"2018","journal-title":"Clin. Epigenetics"},{"key":"B56","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1038\/leu.2014.296","article-title":"A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations","volume":"29","author":"Zhou","year":"2015","journal-title":"Leukemia"},{"key":"B57","doi-asserted-by":"publisher","first-page":"109661","DOI":"10.1016\/j.isci.2024.109661","article-title":"The trogocytosis of neutrophils on initial transplanted tumor in mice","volume":"27","author":"Zhu","year":"2024","journal-title":"iScience"},{"key":"B58","doi-asserted-by":"publisher","first-page":"1527198","DOI":"10.3389\/fpubh.2025.1527198","article-title":"Global, regional and national epidemiological trends of multiple myeloma from 1990 to 2021: a systematic analysis of the global burden of disease study 2021","volume":"13","author":"Zhuge","year":"2025","journal-title":"Front. Public Health"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1613631\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T04:10:46Z","timestamp":1756354246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1613631\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,28]]},"references-count":58,"alternative-id":["10.3389\/fgene.2025.1613631"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1613631","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,28]]},"article-number":"1613631"}}