IGHV1 usage is associated with lymphadenopathy and aggressive disease in the TCL1 mouse model for chronic lymphocytic leukemia

IGHV1 usage is associated with lymphadenopathy and aggressive disease in the TCL1 mouse model for chronic lymphocytic leukemia | 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 IGHV1 usage is associated with lymphadenopathy and aggressive disease in the TCL1 mouse model for chronic lymphocytic leukemia Stephan Drothler, Christian Scherhäufl, Carina Suete, Thomas Parigger, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6647193/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract TCL1 mice are the most commonly used preclinical model for chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by clonal CD5 + B-lymphocyte accumulation. B-cell receptor (BCR) sequencing identifies two important risk markers, immunoglobulin heavy chain variable region (IGHV) mutational status and receptor stereotypy. Despite the clinical importance in patients, no broad examinations of BCR repertoires have been conducted in TCL1 mice. We analysed BCR repertoires of 85 TCL1 mice, primarily comprising CLL clones using IGHV1 and IGHV11 (27.3% and 49.1% of CLL clones, respectively). Interestingly, TCL1 mice with dominant IGHV1 CLL clones showed significantly higher levels of CD4 + T-cells, and increased exhaustion levels (PD-1) on splenic CD8 + T-cells compared to IGHV11 CLL clones. Furthermore, cancer related pathways (p53, MTORC and KRAS) were distinctly regulated in IGHV1 CLL clones which also exhibited significantly decreased survival (hazard ratio 2.6) in female mice. Additionally, mice with dominant IGHV1 CLL clones displayed an almost twofold inguinal lymph node enlargement. In conclusion, we identified molecular, phenotypical and immunological differences between IGHV1 and IGHV11 CLL clones, which are key to consider for preclinical studies using the TCL1 mouse model. Furthermore, our data suggests that IGHV1 CLL clones model the nodal form of human CLL. Biological sciences/Cancer/Haematological cancer/Leukaemia/Chronic lymphocytic leukaemia Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cancer/Cancer models Biological sciences/Cancer/Tumour immunology CLL TCL1 mouse model cancer microenvironment lymphadenopathy translational research Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementFigures.docx SupplementTables.xlsx Cite Share Download PDF Status: Published Journal Publication published 10 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 21 Aug, 2025 Reviews received at journal 20 Aug, 2025 Reviews received at journal 18 Aug, 2025 Reviews received at journal 07 Aug, 2025 Reviewers agreed at journal 01 Aug, 2025 Reviewers agreed at journal 30 Jul, 2025 Reviewers agreed at journal 30 Jul, 2025 Reviewers invited by journal 30 Jul, 2025 Editor invited by journal 24 Jul, 2025 Editor assigned by journal 03 Jun, 2025 Submission checks completed at journal 15 May, 2025 First submitted to journal 15 May, 2025 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-6647193","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":472489914,"identity":"c785f358-d5b9-49da-b6df-9b667debed3c","order_by":0,"name":"Stephan Drothler","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Stephan","middleName":"","lastName":"Drothler","suffix":""},{"id":472489915,"identity":"f77cda63-4bd2-419f-bb43-e285919a725c","order_by":1,"name":"Christian Scherhäufl","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Scherhäufl","suffix":""},{"id":472489916,"identity":"8267d96c-75bf-4082-9e4c-a1cf06ca492a","order_by":2,"name":"Carina Suete","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Carina","middleName":"","lastName":"Suete","suffix":""},{"id":472489917,"identity":"799f9929-a760-4de5-906d-59fd011d29c6","order_by":3,"name":"Thomas Parigger","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Parigger","suffix":""},{"id":472489920,"identity":"87b0930c-8b40-4e8a-96df-b127b49e6fa3","order_by":4,"name":"Franz Josef Gassner","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Franz","middleName":"Josef","lastName":"Gassner","suffix":""},{"id":472489921,"identity":"fe62112a-a484-4c5c-b465-724b3cc7e7d6","order_by":5,"name":"Lisa Pleyer","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Pleyer","suffix":""},{"id":472489922,"identity":"1ee3d101-1224-4361-8777-3bccca0ce5b4","order_by":6,"name":"Alexander Egle","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Egle","suffix":""},{"id":472489923,"identity":"f50cedbd-595e-4cd6-89e4-3a8e84891b0c","order_by":7,"name":"Richard Greil","email":"","orcid":"","institution":"Department of Internal Medicine III , Paracelsus Medical University, Salzburg Cancer Research Institute - 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Laboratory for Immunological and Molecular Cancer Research (LIMCR), Cancer Cluster Salzburg","correspondingAuthor":true,"prefix":"","firstName":"Nadja","middleName":"","lastName":"Zaborsky","suffix":""}],"badges":[],"createdAt":"2025-05-12 13:39:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6647193/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6647193/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-23109-5","type":"published","date":"2025-11-10T15:58:37+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85756401,"identity":"dfe09117-acd0-4e8e-84c2-2c54df9f531a","added_by":"auto","created_at":"2025-07-01 10:49:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":566106,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design, clonality, diversity and survival analyses. \u003cstrong\u003e(A)\u003c/strong\u003eProcessing pipeline from organ sample to individual clones. BCR clones ≥ 5% were defined as CLL clones, whereas clones \u0026lt; 5% were considered as B-cells and consequently labelled as miscellaneous (“Misc”) (see Methods). \u003cstrong\u003e(B)\u003c/strong\u003e Alluvial plot of IGHV, IGHD, and IGHJ gene usage in TCL1 mouse derived CLL clones (n = 166), labelled respective IGH genes. \u003cstrong\u003e(C)\u003c/strong\u003e N-nucleotide insertion (summed N1 and N2 nucleotides) for different CLL clones IGHV1 (27%), IGHV11 (49%) and IGHV12 (11%). Wilcoxon test was used for significance computation. \u003cstrong\u003e(D)\u003c/strong\u003e Sequence similarity (LV score) of aaCDR3 regions of all IGHV1, IGHV11 and IGHV12 clones. LV values were adjusted for clone fraction and 100 randomly selected aaCDR3 sequences were compared (see Methods). \u003cstrong\u003e(E)\u003c/strong\u003eKaplan-Meier survival curves, grouped by IGHV-genes IGHV11 (n = 30), IGHV12 (n = 9) and IGHV1 (n = 22), with a dominant clone \u0026gt; 50%. Individual strata were compared pairwise using log-rank tests with Benjamini-Hochberg false discovery adjustment for multiple comparisons. Hazard ratio (HR) was calculated for significant groups. \u003cstrong\u003e(F) \u003c/strong\u003eKaplan-Meier survival curves, of IGHV11 and IGHV1 stratified by sex, with a dominant clone \u0026gt; 50% (IGHV11 female n = 13, IGHV11 male n = 17, IGHV1 female n = 16, IGHV1 male n = 6). Individual strata were compared pairwise using log-rank tests with Benjamini-Hochberg false discovery adjustment for multiple comparisons. Hazard ratio (HR) was calculated for significant groups. \u003cstrong\u003e(G)\u003c/strong\u003eBar chart summarizing sex distribution of IGHV1 and IGHV11 mice, Fisher’s Exact Test was used to compare differences in sex distribution.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6647193/v1/b4867fdf3d2788753b74b14e.png"},{"id":85756403,"identity":"832e57eb-2f13-465a-9ea6-aba33fb46113","added_by":"auto","created_at":"2025-07-01 10:49:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":321946,"visible":true,"origin":"","legend":"\u003cp\u003eTranscriptome analysis of TCL1 mice. \u003cstrong\u003e(A)\u003c/strong\u003e Principle component analysis of transcriptome analysis from IGHV11 (n = 9) and IGHV1 (n = 4) mice from sorted CD5+CD19+ splenocytes. \u003cstrong\u003e(B)\u003c/strong\u003e Volcano plot indicating differentially expressed genes of IGHV11 (n = 9) and IGHV1 (n = 4) mice from sorted CD5+CD19+ splenocytes. Genes up- or downregulated with a fold change ≥ 2 and an FDR \u0026lt; 0.05 are depicted in red. \u003cstrong\u003e(C)\u003c/strong\u003e Enriched MSigDB Hallmark pathways between IGHV11 (n = 9) and IGHV1 (n = 4) mice from sorted CD5+CD19+ splenocytes. Only significantly enriched pathways are depicted (padj. \u0026lt; 0.05). \u003cstrong\u003e(D)\u003c/strong\u003e Gene set enrichment analysis of three gene sets, each tested IGHV11 versus IGHV1. B1a and B2 specific gene sets were defined by Mabbot et al [15]. IgH-TEµ CLL B1a gene set was published by Singh et al. [16].\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6647193/v1/6fb096d20e47920fc4f21519.png"},{"id":85756407,"identity":"f4bee845-1de4-4c5a-9422-a3ada05ce40f","added_by":"auto","created_at":"2025-07-01 10:49:20","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":277759,"visible":true,"origin":"","legend":"\u003cp\u003eFlow cytometric analysis of TCL1 mice \u003cstrong\u003e(A + B)\u003c/strong\u003e Representative gating strategy for CD8+/CD4+ T-cell subsets (PD1+, CM, EM and naive) and flow cytometry results of SPL from mice with dominant IGHV11 (n = 6) and IGHV1 (n = 8) CLL clones. Wilcoxon test was used to compare IGHV11 and IGHV1 data.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6647193/v1/73a7265f31d9b2f587c96808.png"},{"id":85756409,"identity":"708e2646-59a7-4917-b9bc-51d80f2613bf","added_by":"auto","created_at":"2025-07-01 10:49:20","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":498941,"visible":true,"origin":"","legend":"\u003cp\u003eLN migration of IGHV11 and IGHV1 clones. \u003cstrong\u003e(A) \u003c/strong\u003ePaired dot plot comparing the dominant clone of matched SPL (n = 18; IGHV11 n = 9; IGHV1 n = 9) and LN (n = 18) samples. \u003cstrong\u003e(B)\u003c/strong\u003eRepresentative pictures of LNs from mice with a dominant IGHV11 (ID: 813) and IGHV1 (ID: 537) clone. \u003cstrong\u003e(C)\u003c/strong\u003e Dot plot comparing LN size, and dominant clone in SPL and LN of mice with analysed LN B-cell repertoire of IGHV11 (n = 9) and IGHV1 (n = 8, LN size of one mouse not measurable). \u003cstrong\u003e(D)\u003c/strong\u003e Dot plot displaying LN size based on BCR repertoire of LN if available or the initially sequenced organ of IGHV11 (n = 25) and IGHV1 (n = 25) mice. Wilcoxon test was used to compare IGHV11 and IGHV1 data.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6647193/v1/f87886fcd80c12532f8fcca9.png"},{"id":85756405,"identity":"3f6b6cbd-af24-4d41-956e-bca232bbc82f","added_by":"auto","created_at":"2025-07-01 10:49:20","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":472316,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementFigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-6647193/v1/5fc9653814b345684aad71f3.docx"},{"id":85757623,"identity":"07b26d60-552f-4683-b75e-def546a0e514","added_by":"auto","created_at":"2025-07-01 10:57:20","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28014,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6647193/v1/0530c13e8379c982eeca899f.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"IGHV1 usage is associated with lymphadenopathy and aggressive disease in the TCL1 mouse model for chronic lymphocytic leukemia","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"CLL, TCL1 mouse model, cancer microenvironment, lymphadenopathy, translational research","lastPublishedDoi":"10.21203/rs.3.rs-6647193/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6647193/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTCL1 mice are the most commonly used preclinical model for chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by clonal CD5\u003csup\u003e+\u003c/sup\u003e B-lymphocyte accumulation. B-cell receptor\u0026nbsp;(BCR) sequencing identifies two important risk markers, immunoglobulin heavy chain variable region (IGHV) mutational status and receptor stereotypy. Despite the clinical importance in patients, no broad examinations of BCR repertoires have been conducted in TCL1 mice.\u0026nbsp; We analysed BCR repertoires of 85 TCL1 mice, primarily comprising CLL clones using IGHV1 and IGHV11 (27.3% and 49.1% of CLL clones, respectively). Interestingly, TCL1 mice with dominant IGHV1 CLL clones showed significantly higher levels of CD4\u003csup\u003e+\u003c/sup\u003e T-cells, and increased exhaustion levels (PD-1) on splenic CD8\u003csup\u003e+\u003c/sup\u003e T-cells compared to IGHV11 CLL clones. Furthermore, cancer related pathways (p53, MTORC and KRAS) were distinctly regulated in IGHV1 CLL clones which also exhibited significantly decreased survival (hazard ratio 2.6) in female mice. Additionally, mice with dominant IGHV1 CLL clones displayed an almost twofold inguinal lymph node enlargement. In conclusion, we identified molecular, phenotypical and immunological differences between IGHV1 and IGHV11 CLL clones, which are key to consider for preclinical studies using the TCL1 mouse model. Furthermore, our data suggests that IGHV1 CLL clones model the nodal form of human CLL.\u003c/p\u003e","manuscriptTitle":"IGHV1 usage is associated with lymphadenopathy and aggressive disease in the TCL1 mouse model for chronic lymphocytic leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-01 10:49:15","doi":"10.21203/rs.3.rs-6647193/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-22T03:58:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-20T21:15:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-18T08:58:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-08T00:54:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"20544398373044083192018268460526388453","date":"2025-08-01T15:30:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"288797276585140343097589375583683805361","date":"2025-07-31T01:36:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8730223163873014375430766802921550328","date":"2025-07-30T18:16:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-30T17:43:53+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-24T07:40:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-04T03:22:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-15T08:58:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-05-15T08:56:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3eeade1a-8506-45c2-9999-8c9836da7d64","owner":[],"postedDate":"July 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":50176084,"name":"Biological sciences/Cancer/Haematological cancer/Leukaemia/Chronic lymphocytic leukaemia"},{"id":50176085,"name":"Biological sciences/Cancer/Cancer microenvironment"},{"id":50176086,"name":"Biological sciences/Cancer/Cancer models"},{"id":50176087,"name":"Biological sciences/Cancer/Tumour immunology"}],"tags":[],"updatedAt":"2025-11-17T16:07:00+00:00","versionOfRecord":{"articleIdentity":"rs-6647193","link":"https://doi.org/10.1038/s41598-025-23109-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-11-10 15:58:37","publishedOnDateReadable":"November 10th, 2025"},"versionCreatedAt":"2025-07-01 10:49:15","video":"","vorDoi":"10.1038/s41598-025-23109-5","vorDoiUrl":"https://doi.org/10.1038/s41598-025-23109-5","workflowStages":[]},"version":"v1","identity":"rs-6647193","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6647193","identity":"rs-6647193","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}