VISTA mediates the progression of myelodysplastic syndrome

VISTA mediates the progression of myelodysplastic 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 Article VISTA mediates the progression of myelodysplastic syndrome Raymond J. Zhang, Hyundong Yoon, Qianni Hu, Carly M. Fielder, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8982883/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 11 You are reading this latest preprint version Abstract Myelodysplastic syndrome (MDS) is characterized by progressive cytopenias and a substantial risk of transformation to acute myeloid leukemia. Immune dysregulation is central to the pathogenesis of MDS, and immune suppression is often associated with disease progression. However, immunotherapies such as anti-programmed cell death protein-1 therapy have shown limited efficacy in patients, indicating an incomplete understanding of immune suppression in MDS. To better characterize the immune features of MDS, we performed extensive immune phenotyping of MDS patient bone marrow (BM). We demonstrate that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint, is upregulated in MDS patients by CD34+ blasts and granulocytic myeloid-derived suppressor cells (G-MDSCs) compared to healthy controls, and G-MDSC VISTA expression positively correlates with T cell suppression. In studies employing the NUP98-HOXD13 transgenic MDS mouse model, genetic deletion of VISTA delays the progression of anemia and decreases the rate of death due to severe cytopenias. Assessment of MDS mice reveals that VISTA deletion reduces BM populations of G-MDSCs and reverses the suppression of T cells and macrophages. Together, our findings suggest that VISTA may augment G-MDSC-mediated immune suppression and significantly contribute to ineffective hematopoiesis in MDS. Biological sciences/Cancer/Haematological cancer/Myelodysplastic syndrome Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome Biological sciences/Immunology/Adaptive immunity/Immune tolerance Health sciences/Medical research/Translational research Biological sciences/Immunology/Immunotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations Yes there is potential conflict of interest. Supplementary Files SupplementaryTable5FINAL.xlsx Supplementary Table 5 SupplementaryInformationFINAL.pdf Supplementary Information Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 23 Mar, 2026 Review # 1 received at journal 22 Mar, 2026 Review # 2 received at journal 21 Mar, 2026 Review # 3 received at journal 16 Mar, 2026 Reviewer # 3 agreed at journal 05 Mar, 2026 Reviewer # 2 agreed at journal 04 Mar, 2026 Reviewer # 1 agreed at journal 04 Mar, 2026 Reviewers invited by journal 04 Mar, 2026 Editor assigned by journal 27 Feb, 2026 Submission checks completed at journal 27 Feb, 2026 First submitted to journal 26 Feb, 2026 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-8982883","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":600407017,"identity":"2f2fc261-b7ae-4b05-ae5f-6c741f1e5484","order_by":0,"name":"Raymond J. Zhang","email":"","orcid":"https://orcid.org/0000-0001-6329-7225","institution":"Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"Raymond","middleName":"J.","lastName":"Zhang","suffix":""},{"id":600407018,"identity":"4289e194-e7e0-4644-91d5-825b49d3c13a","order_by":1,"name":"Hyundong Yoon","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hyundong","middleName":"","lastName":"Yoon","suffix":""},{"id":600407019,"identity":"4f7c4153-c694-4794-9047-0b83f3d5ff81","order_by":2,"name":"Qianni Hu","email":"","orcid":"","institution":"University of Manitoba","correspondingAuthor":false,"prefix":"","firstName":"Qianni","middleName":"","lastName":"Hu","suffix":""},{"id":600407020,"identity":"0f297486-e707-4aed-b558-c1b77b08ad13","order_by":3,"name":"Carly M. Fielder","email":"","orcid":"","institution":"Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"Carly","middleName":"M.","lastName":"Fielder","suffix":""},{"id":600407021,"identity":"66c045a9-30f3-4d1f-811a-6e730752d216","order_by":4,"name":"Anjali Raman","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Anjali","middleName":"","lastName":"Raman","suffix":""},{"id":600407022,"identity":"3f63a4a6-4730-41ed-be34-2a9ea5b2ebe2","order_by":5,"name":"Emily F. Mason","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"F.","lastName":"Mason","suffix":""},{"id":600407023,"identity":"c8277675-91fe-4e5d-9507-eb77933b0e13","order_by":6,"name":"Haley E. Ramsey","email":"","orcid":"https://orcid.org/0009-0007-1201-250X","institution":"Department of Internal Medicine, Vanderbilt University School of Medicine, Vanderbilt- Ingram Cancer Center, Nashville, TN","correspondingAuthor":false,"prefix":"","firstName":"Haley","middleName":"E.","lastName":"Ramsey","suffix":""},{"id":600407024,"identity":"7d490e82-8150-4654-83e9-2e1d9326fd7f","order_by":7,"name":"Agnieszka E. Gorska","email":"","orcid":"","institution":"Vanderbilt University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Agnieszka","middleName":"E.","lastName":"Gorska","suffix":""},{"id":600407025,"identity":"54703d58-cd14-4534-988f-53d19710ffde","order_by":8,"name":"David Zhang","email":"","orcid":"https://orcid.org/0009-0009-2891-4334","institution":"Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Zhang","suffix":""},{"id":600407026,"identity":"f7d253f7-955c-40d2-8c66-b4a3e5d4cb39","order_by":9,"name":"Carlos H. Serezani","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Carlos","middleName":"H.","lastName":"Serezani","suffix":""},{"id":600407027,"identity":"3a09f744-dc67-453b-b56f-4fde07ec2ed1","order_by":10,"name":"Michael R. Savona","email":"","orcid":"","institution":"Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"R.","lastName":"Savona","suffix":""},{"id":600407028,"identity":"0f65a3c8-1651-4b3d-8e6e-f8c5c2f729ee","order_by":11,"name":"Paul Brent Ferrell","email":"","orcid":"https://orcid.org/0000-0003-1140-9154","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"Brent","lastName":"Ferrell","suffix":""},{"id":600407029,"identity":"813a5b2d-800d-4bfa-aeb8-e574f34086f9","order_by":12,"name":"Silvia Park","email":"","orcid":"","institution":"Seoul St. Mary's Hematology Hospital, The Catholic University of Korea College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"","lastName":"Park","suffix":""},{"id":600407030,"identity":"acba533e-cc02-4865-bbd9-6d4631048f6f","order_by":13,"name":"Yoo-jin Kim","email":"","orcid":"","institution":"Seoul St. Mary's Hematology Hospital, College of Medicine, The Catholic University of Korea","correspondingAuthor":false,"prefix":"","firstName":"Yoo-jin","middleName":"","lastName":"Kim","suffix":""},{"id":600407031,"identity":"0fe58bb6-5be9-4ef1-b9a3-f50324ec1731","order_by":14,"name":"Jeffrey C. Rathmell","email":"","orcid":"https://orcid.org/0000-0002-4106-3396","institution":"University of Chicago","correspondingAuthor":false,"prefix":"","firstName":"Jeffrey","middleName":"C.","lastName":"Rathmell","suffix":""},{"id":600407032,"identity":"ccaebdaa-0385-4702-93c2-be3c484246d3","order_by":15,"name":"Peter D. Aplan","email":"","orcid":"https://orcid.org/0000-0001-5686-9969","institution":"NIH/NCI","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"D.","lastName":"Aplan","suffix":""},{"id":600407016,"identity":"fa52e6ef-7b44-49aa-9c2d-ee42f510843d","order_by":16,"name":"Tae Kon Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYJACxgaGBB4G9gYilfPAtfAcIFELA4NEApFa7NkPH2CcwZAmozvzjZnUjRoGOfP+BQRs4UlLYNzAkMNjdjvHTDrnGIOxzI0HhByWY8D4gKECqCUtTTq3gSFxhsQBAlr433+AaLl5jFgtEjkMEIfdYD4G0cLfQEDLjWcGB2cYpPGYnUk+bJ1zTMJYQgK/Dgb2/uSHD3sqku3Njh9svJ1TYyMnwU/AYSBwgMEAzpYgIYIQgBhbRsEoGAWjYEQBAG7ePLk067DZAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-5182-3870","institution":"Vanderbilt University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Tae","middleName":"Kon","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2026-02-27 03:15:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8982883/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8982883/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104311204,"identity":"19a5cc4b-917b-45df-8546-c5b3181e8c9b","added_by":"auto","created_at":"2026-03-10 10:57:05","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":72019,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVSIR transcript is upregulated in MDS bone marrow (BM) and associated with worse survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003e\u003cem\u003eVSIR \u003c/em\u003emRNA expression in whole BM from healthy donors (\u003cem\u003en \u003c/em\u003e= 10) or MDS patients (\u003cem\u003en \u003c/em\u003e= 23). Boxes show median with interquartile range (IQR). Error bars represent 1.5 × IQR. \u003cstrong\u003e(B) \u003c/strong\u003ePearson correlations of \u003cem\u003eVSIR \u003c/em\u003eexpression with \u003cem\u003eSMAD2 \u003c/em\u003eand \u003cem\u003eSMAD3 \u003c/em\u003eexpression in whole MDS ×BM. \u003cstrong\u003e(C) \u003c/strong\u003e\u003cem\u003eVSIR \u003c/em\u003emRNA expression by CD34\u003csup\u003e+\u003c/sup\u003e BM cells isolated from healthy donor (\u003cem\u003en \u003c/em\u003e= 17) or MDS patient (\u003cem\u003en \u003c/em\u003e= 159) BM. \u003cstrong\u003e(D) \u003c/strong\u003eOverall survival of MDS patients with high \u003cem\u003eVSIR \u003c/em\u003eexpression (above mean, \u003cem\u003en \u003c/em\u003e= 80) or low \u003cem\u003eVSIR \u003c/em\u003eexpression (below mean, \u003cem\u003en \u003c/em\u003e= 79). Statistical comparisons of \u003cem\u003eVSIR \u003c/em\u003eexpression were performed using a two-tailed Student’s \u003cem\u003et \u003c/em\u003etest (**\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01, ****\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.0001). Survival analysis was performed using the log-rank test and hazard ratio calculated using a univariate Cox proportional hazard regression model.\u003c/p\u003e","description":"","filename":"FINALFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/46ce03cd7fafdf714f8bbd4e.png"},{"id":104311266,"identity":"202ca572-dcbb-4a51-a6bc-7e61eb64f4b0","added_by":"auto","created_at":"2026-03-10 10:57:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":108439,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImmune phenotyping of MDS bone marrow\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBM cells from healthy donors (n = 8) and MDS patients (n = 26) were assessed by flow cytometry. \u003cstrong\u003e(A) \u003c/strong\u003eFrequencies of CD34\u003csup\u003e+\u003c/sup\u003e cells (blasts), myeloid immune cells (CD11b\u003csup\u003e+\u003c/sup\u003e), T cells (CD45\u003csup\u003ehi\u003c/sup\u003eCD3\u003csup\u003e+\u003c/sup\u003e), and B cells (CD19\u003csup\u003e+\u003c/sup\u003e) after excluding dead cells (% of total live BM cells). \u003cstrong\u003e(B) \u003c/strong\u003eMDS samples were categorized using the Revised International Prognostic Scoring System (IPSS-R) into low-risk (IPSS-R very low and low risk; n = 6) and high-risk (IPSS-R intermediate, high, and very high risk; n = 17) groups to compare frequencies of CD34\u003csup\u003e+\u003c/sup\u003e cells (blasts, % of total live BM cells). \u003cstrong\u003e(C) \u003c/strong\u003eFrequencies of myeloid immune cell subsets (myeloid-derived suppressor cells [MDSCs]: CD11b\u003csup\u003e+\u003c/sup\u003eCD33\u003csup\u003e+\u003c/sup\u003eHLA-DR\u003csup\u003e–\u003c/sup\u003e, monocytic MDSCs [M-MDSCs]: CD11b\u003csup\u003e+\u003c/sup\u003eCD33\u003csup\u003e+\u003c/sup\u003eHLA-DR\u003csup\u003e–\u003c/sup\u003eCD14\u003csup\u003e+\u003c/sup\u003eCD15\u003csup\u003e–\u003c/sup\u003e, granulocytic MDSCs [G-MDSCs]: CD11b\u003csup\u003e+\u003c/sup\u003eCD33\u003csup\u003e+\u003c/sup\u003eHLA-DR\u003csup\u003e–\u003c/sup\u003eCD14\u003csup\u003e–\u003c/sup\u003eCD15\u003csup\u003e+\u003c/sup\u003e, and monocyte/macrophages: CD11b\u003csup\u003e+\u003c/sup\u003eCD14\u003csup\u003e+\u003c/sup\u003eCD68\u003csup\u003e+\u003c/sup\u003e; % of total live BM cells). \u003cstrong\u003e(D) \u003c/strong\u003eFrequencies of CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells (% of total live BM cells). Cell frequency data are shown as median ± IQR. Statistical analyses were performed using Mann-Whitney tests with Holm-Šídák’s multiple comparisons correction or the Kruskal-Wallis test with Dunn’s multiple comparisons tests if \u0026gt;2 groups are being compared. (*\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05, **\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01, ***\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.001, ****\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.0001). \u003cstrong\u003e(E) \u003c/strong\u003eNormalized VISTA expression for each indicated cell subset calculated from asinh-transformed ΔMFI between VISTA and isotype control. Violin plots show median with IQR. Statistical analyses were performed using unpaired Welch’s \u003cem\u003et \u003c/em\u003etests with Holm-Šídák’s multiple comparisons correction (**\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01).\u003c/p\u003e","description":"","filename":"FINALFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/698200abb3da1a05c0301f4b.png"},{"id":104311137,"identity":"1faa3f57-fa70-4e0e-bc5f-b8ecde74e53e","added_by":"auto","created_at":"2026-03-10 10:56:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":65621,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eG-MDSC VISTA expression correlates with BM immune suppression in MDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelation between G-MDSC VISTA expression and the frequency of \u003cstrong\u003e(A) \u003c/strong\u003eT cells (CD45\u003csup\u003ehi\u003c/sup\u003eCD3\u003csup\u003e+\u003c/sup\u003e, % of total live BM cells), \u003cstrong\u003e(B) \u003c/strong\u003eCD4\u003csup\u003e+\u003c/sup\u003e T cells (CD45\u003csup\u003ehi\u003c/sup\u003eCD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e, % of total live BM cells), \u003cstrong\u003e(C) \u003c/strong\u003eCD8\u003csup\u003e+\u003c/sup\u003e T cells (CD45\u003csup\u003ehi\u003c/sup\u003eCD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003e, % of total live BM cells), and \u003cstrong\u003e(D) \u003c/strong\u003eregulatory T cells (Tregs [CD45\u003csup\u003ehi\u003c/sup\u003eCD3\u003csup\u003e+\u003c/sup\u003eCD4\u003csup\u003e+\u003c/sup\u003eCD25\u003csup\u003ehi\u003c/sup\u003eCD127\u003csup\u003e–\u003c/sup\u003e], % of CD4\u003csup\u003e+\u003c/sup\u003e T cells). Plots show ranks of each variable. Statistical analyses were performed using Spearman’s rank correlation.\u003c/p\u003e","description":"","filename":"FINALFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/5cfcc83f1a80b46b10854365.png"},{"id":104311151,"identity":"d3b92856-a685-4246-a6d5-6162d7424cf7","added_by":"auto","created_at":"2026-03-10 10:57:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":129448,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\n\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVISTA contributes to disease progression in murine MDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eHemoglobin, \u003cstrong\u003e(B) \u003c/strong\u003ewhite blood cell count, and \u003cstrong\u003e(C) \u003c/strong\u003emean corpuscular volume of mice measured at the indicated months of age (WT, n = 20; VISTA KO, n = 17; NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA WT, n = 17; NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA KO, n = 23). Data are shown as mean ± SEM. Statistical significance was determined by mixed-effects model with Holm-Šídák’s multiple comparisons test. Asterisks represent significant difference between NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA WT and NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA KO groups at the indicated timepoint (*\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05, **\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01). Wright-Giemsa-stained BM cytospins from \u003cstrong\u003e(D) \u003c/strong\u003eNHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA WT and \u003cstrong\u003e(E) \u003c/strong\u003eNHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA KO mice showing \u003cstrong\u003e(i, ii) \u003c/strong\u003edysplastic myeloid elements with abnormal nuclear lobation and \u003cstrong\u003e(iii) \u003c/strong\u003edysplastic erythroid elements with multinucleation. \u003cstrong\u003e(F) \u003c/strong\u003eKaplan-Meier plot showing leukemia-free survival of animals over a 12-month study period. Tick marks represent censored subjects, which were euthanized at 7 months of age for further analysis. \u003cstrong\u003e(G) \u003c/strong\u003eKaplan-Meier plot showing leukemia progression in NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA WT and NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA KO mice. Tick marks represent censored deaths with no evidence of leukemia progression. \u003cstrong\u003e(H) \u003c/strong\u003eKaplan-Meier plot showing deaths associated with severe cytopenias without evidence of leukemia progression. Tick marks represent censored events where evidence of leukemia progression was present. Statistical analyses of Kaplan-Meier plots were performed using logrank (Mantel-Cox) tests to determine \u003cem\u003ep\u003c/em\u003e-value.\u003c/p\u003e","description":"","filename":"FINALFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/59b0624619b54b9004b15dfa.png"},{"id":104311224,"identity":"f3fdb9ee-d6df-4ac2-817e-5651fc11426d","added_by":"auto","created_at":"2026-03-10 10:57:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":225340,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eVISTA contributes to BM immune suppression in murine MDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBM cells were collected from WT (n = 12), VISTA KO (n = 4), NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA WT (n = 5), and NHD13\u003csup\u003eT\u003c/sup\u003eg/VISTA KO (n = 10) mice at 7 months of age and assessed by flow cytometry. Frequencies and representative gating of \u003cstrong\u003e(A) \u003c/strong\u003emyeloid cells (CD11b\u003csup\u003e+\u003c/sup\u003e, % of live CD45\u003csup\u003e+\u003c/sup\u003e BM cells), \u003cstrong\u003e(B) \u003c/strong\u003eM-MDSCs (CD11b\u003csup\u003e+\u003c/sup\u003eMHC-II\u003csup\u003e–/lo\u003c/sup\u003eLy6C\u003csup\u003e+\u003c/sup\u003eLy6G\u003csup\u003e–\u003c/sup\u003e) and G-MDSCs (CD11b\u003csup\u003e+\u003c/sup\u003eMHC-II\u003csup\u003e–/lo\u003c/sup\u003eLy6C\u003csup\u003elo\u003c/sup\u003eLy6G\u003csup\u003e+\u003c/sup\u003e, % of live CD45\u003csup\u003e+\u003c/sup\u003e BM cells), \u003cstrong\u003e(C) \u003c/strong\u003emacrophages (CD11b\u003csup\u003e+\u003c/sup\u003eF4/80\u003csup\u003ehi\u003c/sup\u003e, % of live CD45\u003csup\u003e+\u003c/sup\u003e BM cells), \u003cstrong\u003e(D) \u003c/strong\u003emacrophage subsets (M1-like: MHC-II\u003csup\u003e+\u003c/sup\u003eCD206\u003csup\u003e–\u003c/sup\u003e, M2-like: MHC-II\u003csup\u003e–\u003c/sup\u003eCD206\u003csup\u003e+\u003c/sup\u003e, and resting: MHC-II\u003csup\u003e–\u003c/sup\u003eCD206\u003csup\u003e–\u003c/sup\u003e, % of total macrophages), \u003cstrong\u003e(E) \u003c/strong\u003eT cells (CD3\u003csup\u003e+\u003c/sup\u003e) and B cells (CD19\u003csup\u003e+\u003c/sup\u003e, % of live CD45\u003csup\u003e+\u003c/sup\u003e BM cells), and \u003cstrong\u003e(F) \u003c/strong\u003eT cell subsets (CD4\u003csup\u003e+\u003c/sup\u003e or CD8\u003csup\u003e+\u003c/sup\u003e, % of live CD45\u003csup\u003e+\u003c/sup\u003e BM cells). Data are shown as median ± IQR. Statistical analyses were performed using the Kruskal-Wallis test with Dunn’s multiple comparisons testing (*\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05, **\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01, ***\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"FINALFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/d81f4adaba4621dba0ec9b5d.png"},{"id":105034578,"identity":"cdbe3f80-eaf5-4482-9a6d-cb47cbcaafaf","added_by":"auto","created_at":"2026-03-20 07:23:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1239642,"visible":true,"origin":"","legend":"Article File","description":"","filename":"MainTextFINALv2.1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1_covered_432815ff-6760-4002-a558-a3c4846d4037.pdf"},{"id":104311143,"identity":"755dc413-af32-4aba-bc2e-137d5bb3651d","added_by":"auto","created_at":"2026-03-10 10:56:58","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14505,"visible":true,"origin":"","legend":"Supplementary Table 5","description":"","filename":"SupplementaryTable5FINAL.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/5ac57ae3ba4564ea58790194.xlsx"},{"id":104311138,"identity":"a5f0f512-c1c4-42ef-ad95-c075c2ce40e2","added_by":"auto","created_at":"2026-03-10 10:56:55","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":962064,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryInformationFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8982883/v1/e771fcb1035386b893bc295b.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential conflict of interest.","formattedTitle":"VISTA mediates the progression of myelodysplastic syndrome","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8982883/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8982883/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Myelodysplastic syndrome (MDS) is characterized by progressive cytopenias and a substantial risk of transformation to acute myeloid leukemia. Immune dysregulation is central to the pathogenesis of MDS, and immune suppression is often associated with disease progression. However, immunotherapies such as anti-programmed cell death protein-1 therapy have shown limited efficacy in patients, indicating an incomplete understanding of immune suppression in MDS. To better characterize the immune features of MDS, we performed extensive immune phenotyping of MDS patient bone marrow (BM). We demonstrate that V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint, is upregulated in MDS patients by CD34+ blasts and granulocytic myeloid-derived suppressor cells (G-MDSCs) compared to healthy controls, and G-MDSC VISTA expression positively correlates with T cell suppression. In studies employing the NUP98-HOXD13 transgenic MDS mouse model, genetic deletion of VISTA delays the progression of anemia and decreases the rate of death due to severe cytopenias. Assessment of MDS mice reveals that VISTA deletion reduces BM populations of G-MDSCs and reverses the suppression of T cells and macrophages. Together, our findings suggest that VISTA may augment G-MDSC-mediated immune suppression and significantly contribute to ineffective hematopoiesis in MDS.","manuscriptTitle":"VISTA mediates the progression of myelodysplastic syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 10:55:08","doi":"10.21203/rs.3.rs-8982883/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-03-23T10:50:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-22T21:28:42+00:00","index":1,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-22T00:28:56+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-16T23:18:37+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-05T17:44:17+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-04T14:25:41+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-04T11:46:01+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-03-04T06:58:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-27T12:21:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-27T11:55:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2026-02-27T03:12:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"leukemia","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"leu","sideBox":"Learn more about [Leukemia](http://www.nature.com/leu/)","snPcode":"41375","submissionUrl":"https://mts-leu.nature.com/cgi-bin/main.plex","title":"Leukemia","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d1800fa8-775b-4944-8569-f0cc167b601b","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":63891372,"name":"Biological sciences/Cancer/Haematological cancer/Myelodysplastic syndrome"},{"id":63891373,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Myelodysplastic syndrome"},{"id":63891374,"name":"Biological sciences/Immunology/Adaptive immunity/Immune tolerance"},{"id":63891375,"name":"Health sciences/Medical research/Translational research"},{"id":63891376,"name":"Biological sciences/Immunology/Immunotherapy"}],"tags":[],"updatedAt":"2026-03-23T10:57:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 10:55:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8982883","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8982883","identity":"rs-8982883","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}