Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma

Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma Ariosto Siqueira Silva, Rafael Canevarolo, Praneeth Reddy Sudalagunta, and 31 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6306816/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract We demonstrate that carcinogenesis and multi-therapy resistance in multiple myeloma (MM)—a treatable yet incurable plasma cell malignancy—are driven by epigenetic dysregulation. In this new paradigm, genomic and cytogenetic events unlock epigenetic plasticity, reshaping MM cell biology to evade tumor microenvironment constraints and therapeutic pressure. These conclusions are derived from a newly assembled cohort of nearly 1,000 patients, spanning premalignant to late-stage refractory MM, comprehensively characterized at molecular and clinical levels. Our findings provide a unifying framework to explain inter-patient genomic heterogeneity and the emergence of therapy resistance in sequential samples without new genomic alterations. In conclusion, we propose targeting epigenetic plasticity-mediated plasma cell evasion as a promising therapeutic strategy in MM. Biological sciences/Cancer/Haematological cancer/Myeloma Biological sciences/Genetics/Epigenetics Biological sciences/Genetics/Gene expression multiple myeloma epigenetic plasticity carcinogenesis malignant transformation multi-therapy resistance epigenetics chromatin accessibility H3K27me3 H3K27ac transcription dysregulation super enhancer pioneer transcription factor therapeutic target MGUS smoldering multiple myeloma single cell multiomics Full Text Additional Declarations Yes there is potential Competing Interest. A.S.S., K.H.S., M.B.M, P.R.S., and R.R.C. report a pending patent related to this work (“Altering epigenetic landscapes control progression and refractory disease states in multiple myeloma”; WO2024097981A1). B.D.S. reports grants, personal fees, and other support from Kite/Gilead, other support from Servier and Pepromene Bio, personal fees and other support from Jazz, and personal fees from Novartis, Deciphera, Takeda, Beigene, Pfizer, Bristol Myers Squibb, Amgen, Adaptive, Lilly/Loxo, from Autolus, and Syndax not related to the submitted work. E.M.S. reports grants from the NIH NCI not related to the submitted work. J.B. reports research funding to the institution from Bristol Myers Squibb and WindMIL Therapeutics, outside the submitted work; Also, member of advisory board for Janssen, and speaker’s bureau for Amgen, Bristol Myers Squibb, and Janssen. L.H. reports being a cofounder of Modulation Therapeutics, but this work is not related to the current pipeline at Modulation Therapeutics. K.H.S. reports honoraria from Amgen, Bristol Myers Squibb, Janssen, Adaptive, Sanofi, Regeneron, and Takeda, and research funding to the institution from AbbVie and Karyopharm Therapeutics, not related to the submitted work. M.A. reports grants from Bristol Myers Squibb and other support from Janssen and Sanofi not related to the submitted work. T.N. reports research funding to the institution from Novartis and Karyopharm Therapeutics. O.H. was employed by Aster Insights, a member of the ORIEN/AVATAR consortium, at the time this work was conducted. O.L. reports research funding from National Cancer Institute (NCI)/National Institutes of Health (NIH), US Food and Drug Administration (FDA), Leukemia & Lymphoma Society, Rising Tide Foundation, Memorial Sloan Kettering Cancer Center, Multiple Myeloma Research Foundation (MMRF), International Myeloma Foundation (IMF), Paula and Rodger Riney Foundation, Tow Foundation, Perelman Family Foundation, Myeloma Solutions Fund, Cannon Guzy Family Fund, Amgen, Celgene, Janssen, and Pfizer; has received honoraria for scientific talks/participated in advisory boards for AbbVie, Adaptive, Amgen, Binding Site, Bristol Myers Squibb, Celgene, Cellectis, GSK, Janssen, Juno, and Pfizer; and served on Independent Data Monitoring Committees (IDMC) for international randomized trials by Takeda, Merck, Janssen, and Novartis – all of the above are not related to the submitted work. P.R.S. reports personal fees from FORUS Therapeutics Inc. not related to the submitted work. R.B. reports research funding to the institution from Janssen, Karyopharm, AbbVie, Bristol Myers Squibb, regeneron, outside the submitted work; Also, member of advisory board for Janssen, Karyopharm Therapeutics, and personal fees from Pfizer and Cellectar outside the submitted work. W.S.D. was employed by Aster Insights, which is part of ORIEN/AVATAR consortium, at the time of writing of this manuscript, and receives royalties from patents owned by the Moffitt Cancer Center and licensed to Aster Insights; also reports grants from Karyopharm Therapeutics during the conduct of the study. The other authors declare no competing interests. Supplementary Files TableS2MutationComparisonOtherCohorts.xlsx Table S2 - Mutation Frequencies Compared With Other Cohorts TableS1PatientDemographics.xlsx Table S1 - Patient Demographics TableS3CytogeneticsandMutations.xlsx Table S3 - Cytogenetic Abnormalities and Mutations Cooccurrences TableS6CancerHallmarksandKEGGGSEANES.xlsx Table S6 - Cancer Hallmarks and KEGG GSEA NES TableS7EnrichedDBPs.xlsx Table S7 - Enriched DNA-Binding Proteins TableS10DemographicsscMultiome.xlsx Table S10 - Demographics of Patients With scMultiome Data TableS11PioneerDBPs.xlsx Table S11 - List of Pioneer DNA-Binding Proteins TableS13DemographicsCUTXTag.xlsx Table S13 - Demographics of Patients With CUT&Tag Data TableS8QuadrantsFile.xlsx Table S8 - Clinical, Demographic, and Molecular Information for Patients With Bulk RNA-Seq Data TableS4dNdSUnbalance.xlsx Table S4 - dN/dS Mutations Unbalance TableS17GeneExpxDependencyinMMlinesDepMap.xlsx Table S17 - Gene Expression x Dependency in MM lines (DepMap) TableS18EssentialGenesinMMcelllines.xlsx Table S18 - Essential Genes in MM cell lines TableS19GeneExpressionin8226andB25.xlsx Table S19 - Gene Expression in 8226 and 8226-B25 Cells TableS16213SharedSEs.xlsx Table S16 - List of 213 Super-Enhancer-Regulated Genes Shared by All Samples With CUT&Tag Data TableS5DEGs.xlsx Table S5 - Differentially Expressed Genes Across Disease States TableS9CoxPHModels.xlsx Table S9 - Cox Proportional Hazard Models TableS14CUTXTagListofPeaks.xlsx Table S14 - List of Peaks From CUT&Tag Analysis TableS15SEsROSE.xlsx Table S15 - List of Super-Enhancers Identified TableS12epiAneufinderinferCNVandFISH.xlsx Table S12 - Comparison Between epiAneufinder, inferCNV and FISH Analysis Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6306816","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":437529147,"identity":"909f3f42-b8ea-4078-81ef-decb3d395cf0","order_by":0,"name":"Ariosto Siqueira Silva","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie3QMUvEMBTA8fcoXJccrj2U5iuk3CRk8KOkS1bXDg4phd6iuAqK38Glqz0CNwW/QBfLrQ439gbBhCqINHeOgvlTaJYf7yUAodCfDNX4jyJ7KADiaq1+QYQj7mAAyCYvVXt0kvi0WDsi8CA5uddlvx840BXWyf6xScksWm13wC/pxTRJXvJqSYQEprFe3DTdkszQLSbPn3yjDNanIDSwCCs2b7r8mZaOaJapaUEtWQyW0Aqr7P2hy6/HKX7CLEmIJaCx3M7VN0I9e2UG7V2kJMyRs814lzvDJGMekpq47wfOU3qr2/XbVWdfLH7dFQVn1LPYV+TnwvZrD5OJjk0JhUKhf9MH/5lcPpXJgIgAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3237-9986","institution":"H Lee Moffitt Cancer Center and Research Institute","correspondingAuthor":true,"prefix":"","firstName":"Ariosto","middleName":"Siqueira","lastName":"Silva","suffix":""},{"id":437529148,"identity":"65791a45-30e0-4f19-ac42-2139200d27dc","order_by":1,"name":"Rafael Canevarolo","email":"","orcid":"https://orcid.org/0000-0002-8722-8512","institution":"H. 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Analysis","description":"","filename":"TableS12epiAneufinderinferCNVandFISH.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6306816/v1/152ce45eb5b9544ed9ece1ca.xlsx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nA.S.S., K.H.S., M.B.M, P.R.S., and R.R.C. report a pending patent related to this work (“Altering epigenetic landscapes control progression and refractory disease states in multiple myeloma”; WO2024097981A1).\r\nB.D.S. reports grants, personal fees, and other support from Kite/Gilead, other support from Servier and Pepromene Bio, personal fees and other support from Jazz, and personal fees from Novartis, Deciphera, Takeda, Beigene, Pfizer, Bristol Myers Squibb, Amgen, Adaptive, Lilly/Loxo, from Autolus, and Syndax not related to the submitted work.\r\nE.M.S. reports grants from the NIH NCI not related to the submitted work.\r\nJ.B. reports research funding to the institution from Bristol Myers Squibb and WindMIL Therapeutics, outside the submitted work; Also, member of advisory board for Janssen, and speaker’s bureau for Amgen, Bristol Myers Squibb, and Janssen.\r\nL.H. reports being a cofounder of Modulation Therapeutics, but this work is not related to the current pipeline at Modulation Therapeutics.\r\nK.H.S. reports honoraria from Amgen, Bristol Myers Squibb, Janssen, Adaptive, Sanofi, Regeneron, and Takeda, and research funding to the institution from AbbVie and Karyopharm Therapeutics, not related to the submitted work.\r\nM.A. reports grants from Bristol Myers Squibb and other support from Janssen and Sanofi not related to the submitted work.\r\nT.N. reports research funding to the institution from Novartis and Karyopharm Therapeutics.\r\nO.H. was employed by Aster Insights, a member of the ORIEN/AVATAR consortium, at the time this work was conducted.\r\nO.L. reports research funding from National Cancer Institute (NCI)/National Institutes of Health (NIH), US Food and Drug Administration (FDA), Leukemia \u0026 Lymphoma Society, Rising Tide Foundation, Memorial Sloan Kettering Cancer Center, Multiple Myeloma Research Foundation (MMRF), International Myeloma Foundation (IMF), Paula and Rodger Riney Foundation, Tow Foundation, Perelman Family Foundation, Myeloma Solutions Fund, Cannon Guzy Family Fund, Amgen, Celgene, Janssen, and Pfizer; has received honoraria for scientific talks/participated in advisory boards for AbbVie, Adaptive, Amgen, Binding Site, Bristol Myers Squibb, Celgene, Cellectis, GSK, Janssen, Juno, and Pfizer; and served on Independent Data Monitoring Committees (IDMC) for international randomized trials by Takeda, Merck, Janssen, and Novartis – all of the above are not related to the submitted work.\r\nP.R.S. reports personal fees from FORUS Therapeutics Inc. not related to the submitted work.\r\nR.B. reports research funding to the institution from Janssen, Karyopharm, AbbVie, Bristol Myers Squibb, regeneron, outside the submitted work; Also, member of advisory board for Janssen, Karyopharm Therapeutics, and personal fees from Pfizer and Cellectar outside the submitted work.\r\nW.S.D. was employed by Aster Insights, which is part of ORIEN/AVATAR consortium, at the time of writing of this manuscript, and receives royalties from patents owned by the Moffitt Cancer Center and licensed to Aster Insights; also reports grants from Karyopharm Therapeutics during the conduct of the study.\r\nThe other authors declare no competing interests.","formattedTitle":"Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"multiple myeloma, epigenetic plasticity, carcinogenesis, malignant transformation, multi-therapy resistance, epigenetics, chromatin accessibility, H3K27me3, H3K27ac, transcription dysregulation, super enhancer, pioneer transcription factor, therapeutic target, MGUS, smoldering multiple myeloma, single cell multiomics","lastPublishedDoi":"10.21203/rs.3.rs-6306816/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6306816/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"We demonstrate that carcinogenesis and multi-therapy resistance in multiple myeloma (MM)—a treatable yet incurable plasma cell malignancy—are driven by epigenetic dysregulation. In this new paradigm, genomic and cytogenetic events unlock epigenetic plasticity, reshaping MM cell biology to evade tumor microenvironment constraints and therapeutic pressure. These conclusions are derived from a newly assembled cohort of nearly 1,000 patients, spanning premalignant to late-stage refractory MM, comprehensively characterized at molecular and clinical levels. Our findings provide a unifying framework to explain inter-patient genomic heterogeneity and the emergence of therapy resistance in sequential samples without new genomic alterations. In conclusion, we propose targeting epigenetic plasticity-mediated plasma cell evasion as a promising therapeutic strategy in MM.","manuscriptTitle":"Epigenetic Plasticity Drives Carcinogenesis and Multi-Therapy Resistance in Multiple Myeloma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-15 02:16:48","doi":"10.21203/rs.3.rs-6306816/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"767c0f9a-8a53-4383-a436-3b26dbd9dd70","owner":[],"postedDate":"April 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":46589015,"name":"Biological sciences/Cancer/Haematological cancer/Myeloma"},{"id":46589016,"name":"Biological sciences/Genetics/Epigenetics"},{"id":46589017,"name":"Biological sciences/Genetics/Gene expression"}],"tags":[],"updatedAt":"2025-04-15T02:16:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-15 02:16:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6306816","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6306816","identity":"rs-6306816","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}