Phase separation of AKAP95 regulates oncogenic MLL-fusion driven transcription and its modulation for cancer therapy

Phase separation of AKAP95 regulates oncogenic MLL-fusion driven transcription and its modulation for cancer therapy | 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 Phase separation of AKAP95 regulates oncogenic MLL-fusion driven transcription and its modulation for cancer therapy Wei Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5274238/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract RNA binding proteins (RBPs) have been reported to own genome-wide chromatin binding sites, and are supposed to regulate transcription directly. However, the molecular detail about RBPs regulating transcription is still unclear. Here, we showed the RBP AKAP95 engaged in transcription regulation through tethering itself to nascent RNA on chromatin. Further, phase separation enabled AKAP95 having large spectrum coverage on transcription start sites and meanwhile recruiting RNA polymerase II CTD to activate transcription. This transcription co-activation mechanism was hijacked in MLL rearranged (MLLr) leukemia. AKAP95 was enclosed in the same condensates with MLL1 translocated fragment. It was required for MLLr leukemogenesis, but not for normal and regenerative hematopoiesis, rendering AKAP95 an ideal target for leukemia therapeutics. As an endeavor for modifying condensates, we designed a peptide bridging AKAP95 with protein quality surveillance component HSP70. This peptide successfully impaired AKAP95 phase separation, transcription activation and cancer cell growth, attesting the concept that oncogenic condensates is druggable. Biological sciences/Genetics/Gene regulation Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia transcription RNA-binding protein phase separation MLLr leukemia regulator Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Nature Communications → 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-5274238","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":375016941,"identity":"2b4c41df-883e-4847-bf98-e4fcadfcf5f4","order_by":0,"name":"Wei Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYDACduYDDAwVB8BsCeK0MLMlMDCcIU0LjwIDYxspWgwO8zC/+DjvTp7BAeaDt3kY7PKI0MJ7zHLmtmfFBgfYkq15GJKLCWoxO8yXZsy77XDihgM8ZtI8DAcSGwhr4TEz/jsHpIX/G9FajB8zNoBtYSNOi/1htjTGnmOHE2ceZjO2nGOQTFiLZHvz4Q8/ag4n9h1vfnjjTYUdYS1AwAaJDmYQYUCEepDaD8SpGwWjYBSMghELAB2CP9lG28yfAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Biomedical and Engineering, College of Biology, Hunan University","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-10-16 08:50:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5274238/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5274238/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41467-025-68192-4","type":"published","date":"2026-01-07T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102284805,"identity":"a5472606-9a67-4d11-9d3a-0854b7fdc10d","added_by":"auto","created_at":"2026-02-10 08:07:39","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2711973,"visible":true,"origin":"","legend":"","description":"","filename":"TextFiguresSupplFig.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5274238/v1_covered_b30f3e9f-7816-452c-9675-0074f8d5254b.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Phase separation of AKAP95 regulates oncogenic MLL-fusion driven transcription and its modulation for cancer therapy","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"transcription, RNA-binding protein, phase separation, MLLr leukemia regulator","lastPublishedDoi":"10.21203/rs.3.rs-5274238/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5274238/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"RNA binding proteins (RBPs) have been reported to own genome-wide chromatin binding sites, and are supposed to regulate transcription directly. 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