Fetal Liver-Restricted Leukemic Proliferation Via GATA1s-CSF2RB-MPL Axis In Down Syndrome

Fetal Liver-Restricted Leukemic Proliferation Via GATA1s-CSF2RB-MPL Axis In Down Syndrome | 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 Fetal Liver-Restricted Leukemic Proliferation Via GATA1s-CSF2RB-MPL Axis In Down Syndrome Paresh Vyas, David Cruz Hernandez, Nicolas Papadopoulos, Leila Varghese, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7842540/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 Some childhood cancers can arise in utero and then regress at birth, but the cues that permit malignant proliferation in utero as opposed to postnatal life are often unclear. Transient abnormal myelopoiesis (TAM) is a human fetal liver leukemia driven by GATA1s mutations and a rare exemplar of a spontaneously resolving cancer when blood formation shifts from liver to bone marrow (BM) during development. Here we show that the cytokine receptor CSF2RB is aberrantly upregulated in TAM cells because it is a GATA2 target that escapes repression by GATA1s. Pathologically expressed CSF2RB unexpectedly interacts with the thrombopoietin receptor MPL to prolong JAK-STAT signaling by fetal-liver produced THPO, driving GATA1s-mutant cell expansion. TAM can transform into myeloid leukemia of Down syndrome (ML-DS) upon acquisition of additional mutations. We further show that the ML-DS driver CSF2RB A455D forces MPL dimerization resulting in constitutive JAK-STAT activation, bypassing THPO dependence in the fetal-liver niche, thereby enabling proliferation in the BM. Conversely, base-editing reversion of another ML-DS JAK-STAT-activating mutation, JAK3 A572V, restores THPO dependence. These results identify a cytokine gate that developmentally restricts GATA1s oncogenic competence, reconciling why TAM expands in the fetal liver yet resolves after birth, revealing a niche-specific, therapeutically targetable dependency. Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cell biology/Cell signalling/Growth factor signalling Biological sciences/Developmental biology/Haematopoiesis/Myelopoiesis Biological sciences/Cancer/Haematological cancer/Myeloproliferative disease Full Text Additional Declarations There is NO Competing Interest. Supplementary Files DocumentS1.pdf Extended Figures 1-9 DocumentS2.xlsx Supplementary Table 1-6 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. 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-7842540","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":532415906,"identity":"2b6ae701-ec7f-4e0a-be96-fe7e9a459203","order_by":0,"name":"Paresh Vyas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYLACxgYI9SABSdCAGC3MBiRrYZNAFsSpxZz97MOHP3cwJG44fvxZxcOcbQz8EgmMH34wHDbGpcWyJ93YmPcMUMuZHLMbidtuM0j2HGCW7GE4bIZLi8GBNDZpxjYGY4MDOWxgLQbHGxikGRgO2+DUcv4Z+8+fIC3nnz8rAGs5zMD8G6+WG2lsDLxtDHIGNxLMGKC2sIFswekwyxnPmKV52yTkJG+8MZYAauGR7DnYZtljkI7T++b8aYwff7bZ8PCdT3/48ee223L8EsmHb/yosDZswOUwCCXBoHAAwuKBRBOeiIRLyeMydBSMglEwCkYBAGk7VSQrJspyAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3931-0914","institution":"MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR Oxford Biomedical Research Centre Haematology Theme, Radcliffe Department of Medicine, University of Oxford","correspondingAuthor":true,"prefix":"","firstName":"Paresh","middleName":"","lastName":"Vyas","suffix":""},{"id":532415907,"identity":"eff6edae-8144-4ab7-a7e5-af1079f86006","order_by":1,"name":"David Cruz Hernandez","email":"","orcid":"","institution":"MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford.","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"Cruz","lastName":"Hernandez","suffix":""},{"id":532415908,"identity":"be8cc4d0-5b94-4886-936f-145ade84153e","order_by":2,"name":"Nicolas Papadopoulos","email":"","orcid":"https://orcid.org/0000-0001-7869-862X","institution":"Université catholique de Louvain and de Duve Institute. 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Transient abnormal myelopoiesis (TAM) is a human fetal liver leukemia driven by GATA1s mutations and a rare exemplar of a spontaneously resolving cancer when blood formation shifts from liver to bone marrow (BM) during development. Here we show that the cytokine receptor CSF2RB is aberrantly upregulated in TAM cells because it is a GATA2 target that escapes repression by GATA1s. Pathologically expressed CSF2RB unexpectedly interacts with the thrombopoietin receptor MPL to prolong JAK-STAT signaling by fetal-liver produced THPO, driving GATA1s-mutant cell expansion. TAM can transform into myeloid leukemia of Down syndrome (ML-DS) upon acquisition of additional mutations. We further show that the ML-DS driver CSF2RB A455D forces MPL dimerization resulting in constitutive JAK-STAT activation, bypassing THPO dependence in the fetal-liver niche, thereby enabling proliferation in the BM. Conversely, base-editing reversion of another ML-DS JAK-STAT-activating mutation, JAK3 A572V, restores THPO dependence. These results identify a cytokine gate that developmentally restricts GATA1s oncogenic competence, reconciling why TAM expands in the fetal liver yet resolves after birth, revealing a niche-specific, therapeutically targetable dependency.","manuscriptTitle":"Fetal Liver-Restricted Leukemic Proliferation Via GATA1s-CSF2RB-MPL Axis In Down Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 09:57:07","doi":"10.21203/rs.3.rs-7842540/v1","editorialEvents":[],"status":"published","journal":{"display":false,"email":"[email protected]","identity":"nature","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nature","sideBox":"Learn more about [Nature](http://www.nature.com/nature/)","snPcode":"","submissionUrl":"","title":"Nature","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6347aa08-cc65-4bee-bbd9-d44b87ca10d4","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56594591,"name":"Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute myeloid leukaemia"},{"id":56594592,"name":"Biological sciences/Cancer/Cancer microenvironment"},{"id":56594593,"name":"Biological sciences/Cell biology/Cell signalling/Growth factor signalling"},{"id":56594594,"name":"Biological sciences/Developmental biology/Haematopoiesis/Myelopoiesis"},{"id":56594595,"name":"Biological sciences/Cancer/Haematological cancer/Myeloproliferative disease"}],"tags":[],"updatedAt":"2025-11-25T11:40:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 09:57:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7842540","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7842540","identity":"rs-7842540","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}