Human iPSCs-based modeling unveils chromatin remodeling induced by SETBP1 mutation as a potential initiating factor in GATA2 deficiency

Human iPSCs-based modeling unveils chromatin remodeling induced by SETBP1 mutation as a potential initiating factor in GATA2 deficiency | 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 Human iPSCs-based modeling unveils chromatin remodeling induced by SETBP1 mutation as a potential initiating factor in GATA2 deficiency Alessandra Giorgetti, Oskar Marin-Bejar, Joan Pera, Damià Romero-Moya, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4984522/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Patients with GATA2 deficiency are predisposed to developing myelodysplastic syndrome (MDS), which can progress to acute myeloid leukemia (AML). This progression is often associated with the acquisition of additional cytogenetic and somatic alterations. Mutations in SETBP1 and ASXL1 genes are frequently observed in pediatric GATA2 patients, but their roles in disease progression remain poorly understood. Genome editing of induced pluripotent stem cells (iPSCs) enabled precise reconstruction of mutation combinations found in patients. Here we developed a human hiPSC-based model to study the impact of SETBP1 and ASXL1 mutations in context of GATA2 deficiency. We show that germline heterozygous GATA2 mutation alone showed no significant effect on myeloid development, while the addition of SETBP1 and ASXL1 mutations impaired myelopoiesis, resulting in monocytopenia. We identified a key role of the SETBP1 mutation in promoting chromatin remodeling near genes involved in myeloid neoplasms, which likely initiated the blockage of myeloid differentiation observed in vitro. Motif analysis of more accessible chromatin regions in the SETBP1 and SETBP1/ASXL1 mutant background highlighted an enrichment for MEIS1, PU.1, RUNX1, and HOXA9, implicating these factors in the disease progression. Our study establishes a novel humanized model system for studying GATA2 deficiency. We demonstrate that SETBP1 mutations act as a primary driver in hematopoietic impairment, providing insights that may inform future therapeutic strategies for patients progressing to MDS/AML Biological sciences/Stem cells/Haematopoietic stem cells Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome Biological sciences/Stem cells/Pluripotent stem cells/Induced pluripotent stem cells Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MarinPeraetalSuppMaterials202408026def.pdf Cite Share Download PDF Status: Published Journal Publication published 17 Nov, 2025 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4984522","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":348166505,"identity":"4d6a7fd7-ed92-43c1-898b-5626ed5ffad7","order_by":0,"name":"Alessandra Giorgetti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYFACxgYIzcx84ACPwQEGPnYitUjwMLMlgLWwMYP4CYTtkuBh4DFg4GEgQgt//+LGxxW/bOrs2Xk+HnhTcEcOqIXxw88feEy/8bDZ8GxfGtBhvBsOzjF4ZgzUwizZg89hNw62STb2HAZrOcxjcDixjZmBjYEHjxZ5iJb/QC08D0Ba6kFaGP/g0WJwvrFNsuHHAZAWBpCWBKDD2Jjx2WJ4g7HZsLEhWbLnMJsByC+GbcyMzdIyabi1yJ0//vBhwx87fvb+w48/vPlzR56fvfngxzc2eLwvAXQCYxuKECw94AL8B4DEH/xqRsEoGAWjYIQDAJmQUMh24J3jAAAAAElFTkSuQmCC","orcid":"","institution":"Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)","correspondingAuthor":true,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Giorgetti","suffix":""},{"id":348166506,"identity":"1acc32b7-a94b-4c7b-a5ed-bf3f909786c4","order_by":1,"name":"Oskar Marin-Bejar","email":"","orcid":"","institution":"Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC)","correspondingAuthor":false,"prefix":"","firstName":"Oskar","middleName":"","lastName":"Marin-Bejar","suffix":""},{"id":348166507,"identity":"8894e9fb-9f1c-47f8-91b8-6d3dc420c19f","order_by":2,"name":"Joan Pera","email":"","orcid":"https://orcid.org/0000-0002-6690-3363","institution":"Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)","correspondingAuthor":false,"prefix":"","firstName":"Joan","middleName":"","lastName":"Pera","suffix":""},{"id":348166508,"identity":"e86411b3-fb65-4aca-bc64-a54106d8156a","order_by":3,"name":"Damià Romero-Moya","email":"","orcid":"https://orcid.org/0000-0001-9947-3577","institution":"Regenerative Medicine Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL)","correspondingAuthor":false,"prefix":"","firstName":"Damià","middleName":"","lastName":"Romero-Moya","suffix":""},{"id":348166509,"identity":"34dcb9ba-ebcf-40c7-a85f-f1a98a862bf7","order_by":4,"name":"Eric Torralba","email":"","orcid":"https://orcid.org/0009-0003-7612-2792","institution":"Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC)","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Torralba","suffix":""},{"id":348166510,"identity":"6bac190d-51cc-4e10-a331-42d4de8e5ae7","order_by":5,"name":"Maximiliano Distefano","email":"","orcid":"","institution":"Regenerative Medicine Program, Bellvitge Institute for Biomedical Research (IDIBELL) and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC)","correspondingAuthor":false,"prefix":"","firstName":"Maximiliano","middleName":"","lastName":"Distefano","suffix":""},{"id":348166511,"identity":"9e72cc36-6c0e-4f53-a8a7-62704eb6faf7","order_by":6,"name":"Clara Berenguer Balaguer","email":"","orcid":"","institution":"Endocrine Regulatory Genomics, Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF)","correspondingAuthor":false,"prefix":"","firstName":"Clara","middleName":"Berenguer","lastName":"Balaguer","suffix":""},{"id":348166512,"identity":"a8401776-c088-4c9a-b1d3-a3e6988120f4","order_by":7,"name":"Julio Castaño","email":"","orcid":"https://orcid.org/0000-0002-0712-5856","institution":"4.\tAdvanced therapy platform, Hospital Sant Joan de Deu, SJD Pediatric Cancer Center Barcelona (PCCB). 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