KBTBD4-UM171-CoREST1 Axis Prevents Stress-Induced Aging of Human Hematopoietic Stem Cells

KBTBD4-UM171-CoREST1 Axis Prevents Stress-Induced Aging of Human Hematopoietic Stem Cells | 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 Biological Sciences - Article KBTBD4-UM171-CoREST1 Axis Prevents Stress-Induced Aging of Human Hematopoietic Stem Cells Guy Sauvageau, Maria Florencia Tellechea, Jalila Chagraoui, Jean-François Spinella, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6355173/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 UM171 is a small molecule degrader of CoREST1 and MYC through KBTBD4 E3 ligase activation. It was initially characterized as a potent hematopoietic stem cell (HSC) self-renewal agonist, with more recent evidence suggesting that it may counter aging-associated declines in HSC function. Here, using both scRNAseq and in vivo functional approaches, we provide evidence that several key features of HSC aging, notably reduction in lymphoid differentiation, serial transplantation competency, and quiescence, are modulated by UM171 dosage and subsequent CoREST1 degradation, gradually reaching maximal efficacy at a higher dose of 125nM. In such conditions, lymphoid output per HSC is markedly enhanced and provides robust hematopoiesis even in a stressful environment. Mechanistically, we identify several HSC clusters progressively affected by CoREST1 depletion, the most primitive one reaching peak expression of genes known to distinguish HSCs with superior engraftment potential, such as LMNA, RGCC, VIM, and ID at maximal CoREST1 degradation. Together, these data provide evidence for a rheostat function of the KBTBD4-UM171-CoREST1 axis in regulating HSC aging, counteracting the negative impact of stress. Biological sciences/Stem cells/Haematopoietic stem cells Biological sciences/Stem cells/Self-renewal Biological sciences/Stem cells/Ageing Full Text Additional Declarations Yes there is potential Competing Interest. Except for Guy Sauvageau, the authors declare no competing financial interests. GS is the founder and chief scientist of ExCellThera, a small biotech that owns an exclusive license to UM171. Supplementary Files TableS1.xlsx Dataset 1 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-6355173","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":444841991,"identity":"4089c840-562e-47c1-8393-9e5daef9dd92","order_by":0,"name":"Guy Sauvageau","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYPCDCjjLglgtZ0AEM4iQIFIHYxsRWuQjcgwYf9QcTuzvX3zwM++8w9H80v3HPnyokWDgbz+AVYvhjRwDZp5jhxNn3HiWLM277XDuzDmHmWfOOCbBIHEmAbuWGUAtDGyHjRlunDEAa9lwI5mZmYdNgsGAAbcWxh//DhvL3zj/+TfvHKiWP/+AWvgfYPeLRI4BA2/bYTmD8z1s0rwNUC2MbUAtEthtMeB5VnCYty9dzvAGm5nlnGPpuTNnJBsz9vZJ8EjcwGFLe/LGhz++WfPInT/8+MabGuvcfonExww/vtnI8ffjsOUAh8EBMAvdGTxY1YNsaWCHWs9/AJeaUTAKRsEoGOkAADTVXzf8ktIbAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-4333-7266","institution":"University of Montreal","correspondingAuthor":true,"prefix":"","firstName":"Guy","middleName":"","lastName":"Sauvageau","suffix":""},{"id":444841992,"identity":"95e099c5-bd45-4a11-952c-42575c10a2af","order_by":1,"name":"Maria Florencia Tellechea","email":"","orcid":"","institution":"University of Montreal","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Florencia","lastName":"Tellechea","suffix":""},{"id":444841993,"identity":"5e1b43e0-6567-4fde-8d7f-10a3234c9000","order_by":2,"name":"Jalila Chagraoui","email":"","orcid":"","institution":"University de Montreal","correspondingAuthor":false,"prefix":"","firstName":"Jalila","middleName":"","lastName":"Chagraoui","suffix":""},{"id":444841994,"identity":"8d1bf8e8-add2-4108-8126-e3a5a4281528","order_by":3,"name":"Jean-François Spinella","email":"","orcid":"","institution":"Institute for Research in Immunology and Cancer","correspondingAuthor":false,"prefix":"","firstName":"Jean-François","middleName":"","lastName":"Spinella","suffix":""},{"id":444841995,"identity":"5cc2e06c-b968-453c-8411-c39e0133cb7f","order_by":4,"name":"Nadine Mayotte","email":"","orcid":"","institution":"University of Montreal","correspondingAuthor":false,"prefix":"","firstName":"Nadine","middleName":"","lastName":"Mayotte","suffix":""},{"id":444841996,"identity":"70cd3d69-2da6-4b20-a03b-fa053e23beaf","order_by":5,"name":"Laure Mallinger","email":"","orcid":"","institution":"University of Montreal","correspondingAuthor":false,"prefix":"","firstName":"Laure","middleName":"","lastName":"Mallinger","suffix":""}],"badges":[],"createdAt":"2025-04-01 17:15:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6355173/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6355173/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83531227,"identity":"5e7e5998-4431-410b-b8c7-9971aba4f254","added_by":"auto","created_at":"2025-05-28 05:05:20","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10952950,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Manuscript20250401.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6355173/v1_covered_fc5e26c9-19e7-49ed-8da2-b0e00326d02f.pdf"},{"id":83531104,"identity":"c5da7c45-5fea-44fa-bb76-538594848b37","added_by":"auto","created_at":"2025-05-28 04:57:01","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":9728187,"visible":true,"origin":"","legend":"Dataset 1","description":"","filename":"TableS1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6355173/v1/f30b07a85d57c198ff342c90.xlsx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nExcept for Guy Sauvageau, the authors declare no competing financial interests. 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