Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model

Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model | 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 Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model François Lemonnier, Gamze TARI, Selcen ARI-YUKA, Anja Fischer, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5117296/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 Follicular helper T-cell lymphoma (TFHL) is the most common non-cutaneous T-cell lymphoma in the Western world and is associated with a poor prognosis. Neoplastic cells rely heavily on the tumor microenvironment, demonstrated by the absence of TFHL-derived cell lines, which hinders therapeutic progress. To overcome this limitation, we developed and characterized patient-derived xenograft TFHL (TFHL-PDXs). Fifteen TFHLs were implanted into immunodeficient mice, generating nine PDXs. The tumor microenvironment was detected in the first passage but progressively disappeared in subsequent passages. TET2 mutations persisted in all cases and TFHL-specific mutations were observed in most. The models were treated with azacitidine and patient sensitivity was fully recapitulated. To elucidate the mechanism of action of azacitidine, we analyzed the differences in DNA methylation and gene expression in four TFHL-PDX models. Global DNA hypomethylation occurred in azacitidine-treated cells in drug-sensitive models but not in the resistant one. DNA hypomethylation was associated with global upregulation of gene expression, including that of various cancer-related pathways, suggestive of p53-pathway-mediated cytotoxicity. Overall, the PDXs recapitulated TFHL features and exhibited sensitivity to azacitidine. They also made it possible to decipher the mechanism responsible for the effect of azacitidine, revealing the activation of p53-mediated apoptosis associated with DNA hypomethylation. Biological sciences/Cancer/Cancer models Health sciences/Medical research/Preclinical research Health sciences/Diseases/Haematological diseases/Haematological cancer/Lymphoma/Non-hodgkin lymphoma/T-cell lymphoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations Yes there is potential conflict of interest. Table 1 is available in the Supplementary Files section. Supplementary Files Table1.xlsx Table 1. PDX information 5-aza: azacitidine, BV: brentuximab vedotin, CC200: iberdomide, CC486: oral azacytidine, CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone, CHOP E: CHOP + etoposide, CR: complete response, DHAC: dexamethasone, GEMOX: gemcitabine, oxaliplatin, ICE: ifosfamide, carboplatin, etoposide, NA: not available, PD: progressive disease, SCT, stem cell transplant, SD: stable disease, WT: wildtype Supplementary.pdf 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. 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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-5117296","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":357919020,"identity":"888df55b-3021-49b6-9589-1c626c1865d9","order_by":0,"name":"François Lemonnier","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYBAC9gYwJQFkQQR4GBiYDzAwNsClMADPAZgWZrgWtgSwFqgULi0McC0gMQP8WqQPP3vwo8LCnoGZ+eiGjzvuyPBLn/n4uXDHHaAUdj08fGnmhj1nJBIbmNnSbs4884xHsi93szSQAZRKwKrFnofBTJqxTSKBgZnH7DZv22EegzO8G6SBDJAUdlt42L+BtAAdxv8NrMX+DM/j3yAtPDi18IBtYWxg5mGD2MLDwyZNQEuZJMgvbcxsZjdnArVInGEzs57Z9owHtxb2bRI/Kurs+dmbn9342HbYnr+H+fHtwrY7cri0wAEbMgcYRwcIaUADIC2k6RgFo2AUjILhDAD0YE/1UgPr7gAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-6205-5419","institution":"Henry Mondor Hospital, INSERM U955 Mondor Institute for Biomedical Research, Paris-Est Créteil University","correspondingAuthor":true,"prefix":"","firstName":"François","middleName":"","lastName":"Lemonnier","suffix":""},{"id":357919021,"identity":"d6415462-bc0d-4fe3-b43d-adf6ede3c4c5","order_by":1,"name":"Gamze TARI","email":"","orcid":"","institution":"Mondor Biomedical Research Institute, Team Ortonne, INSERM U955","correspondingAuthor":false,"prefix":"","firstName":"Gamze","middleName":"","lastName":"TARI","suffix":""},{"id":357919022,"identity":"6d175af2-42e1-473c-a202-3a4d09f80b78","order_by":2,"name":"Selcen ARI-YUKA","email":"","orcid":"","institution":"Yildiz Technical University, Department of Bioengineering","correspondingAuthor":false,"prefix":"","firstName":"Selcen","middleName":"","lastName":"ARI-YUKA","suffix":""},{"id":357919023,"identity":"d97ae758-0387-468e-a00a-58e79cf81114","order_by":3,"name":"Anja Fischer","email":"","orcid":"https://orcid.org/0000-0002-7145-2544","institution":"University of Ulm","correspondingAuthor":false,"prefix":"","firstName":"Anja","middleName":"","lastName":"Fischer","suffix":""},{"id":357919024,"identity":"8a37c1e9-5128-4d69-934e-1408c86bcf3c","order_by":4,"name":"Mohamed Chour","email":"","orcid":"https://orcid.org/0009-0006-5755-4620","institution":"Ecole Normale Supérieure de 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Marie-Hélène","middleName":"","lastName":"DELFAU-LARUE","suffix":""},{"id":357919031,"identity":"cedf214c-8f75-41fd-b03b-72f099ecc2e1","order_by":11,"name":"Nicolas ORTONNE","email":"","orcid":"","institution":"APHP, Henri Mondor Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nicolas","middleName":"","lastName":"ORTONNE","suffix":""},{"id":357919032,"identity":"9960a363-2f5f-413e-b81f-834618a5b3ec","order_by":12,"name":"Vincent Alcazer","email":"","orcid":"https://orcid.org/0000-0003-1843-6286","institution":"Cancer Research Center of Lyon","correspondingAuthor":false,"prefix":"","firstName":"Vincent","middleName":"","lastName":"Alcazer","suffix":""},{"id":357919033,"identity":"d8db4b7a-cfef-47dc-9d12-18fc2c6946a0","order_by":13,"name":"Reiner Siebert","email":"","orcid":"https://orcid.org/0000-0001-7433-3703","institution":"Institute of Human Genetics","correspondingAuthor":false,"prefix":"","firstName":"Reiner","middleName":"","lastName":"Siebert","suffix":""},{"id":357919034,"identity":"311744a9-0ca7-47a7-a496-377b72e1e307","order_by":14,"name":"Philippe Gaulard","email":"","orcid":"","institution":"Hôpital Henri Mondor","correspondingAuthor":false,"prefix":"","firstName":"Philippe","middleName":"","lastName":"Gaulard","suffix":""}],"badges":[],"createdAt":"2024-09-19 13:21:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5117296/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5117296/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":68355126,"identity":"8d4d3e50-4f80-4aef-8304-3a72159c93f2","added_by":"auto","created_at":"2024-11-06 11:14:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":522854,"visible":true,"origin":"","legend":"\u003cp\u003ePDX Generation and Characterization A) Schematic representation of PDX development B) PDX recapitulates TFHL symptoms, shown here with circles: enlarged lymph nodules, arrows: high vascularization and splenomegaly C) Heatmap for multiple organ infiltration of different models. Tissue samples of the \u0026nbsp;spleen, lymph nodules, liver, kidneys, lung and skin of each model were evaluated by a \u0026nbsp;pathologist and the degree of infiltration degree described as mild, moderate, or \u0026nbsp;massive. Blood and bone marrow infiltration are described as the percentage of \u0026nbsp;hCD45+CD4+PD1+ cells by flow cytometry. \u0026nbsp;D) Phenotypic characterization of PDX models by Immunohistochemistry. Staining of spleen tissue at passage 1. HES (10X), TFH markers: CD4 (10X), ICOS (20X), PD1 \u0026nbsp;(20X), BCL6 (20X), and CXCL13 (20X), and microenvironment markers: CD8 (10X) and CD20 (10X) E) Phenotypic characterization of PDX models by flow cytometry. Staining of splenocytes from passage 1. Panel: CD45, CD19, CD3, CD8, CD4, ICOS, and PD1\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/98ab2f462a2cade607cd6a60.png"},{"id":68355357,"identity":"e2729c52-2ad1-4fa9-b61e-552c3dfbe2a4","added_by":"auto","created_at":"2024-11-06 11:22:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":353685,"visible":true,"origin":"","legend":"\u003cp\u003eMolecular, Pathological, and Survival Evolution during Passaging\u003c/p\u003e\n\u003cp\u003eA) Evolution of tumor cells and the microenvironment during passaging. IHC Staining of spleen tissue by HES (10X), tumor cell markers: CD4 (10X) and PD1 (20X), and \u0026nbsp;microenvironment markers CD8 (10X) and CD20 (10X) B) Mutational landscape of TFHL-PDX library. The figure presents the distribution of \u0026nbsp;mutations in TET2, DNMT3A, IDH2, RHOA, VAV1, CD28, and PLCG1. Samples \u0026nbsp;represented in dark blue bore at least two TET2 mutations, whereas only one TET2 \u0026nbsp;mutation was detected in samples represented in light blue. DNMT3A R882* variants \u0026nbsp;are represented in dark green, whereas samples represented in light green harbored \u0026nbsp;DNMT3A mutations altering residues V3228 and N612fs. The models were sequenced \u0026nbsp;using different versions of the lymphoma panel: PDX1: V.1.3, PDX6: V.1.3, PDX6Bis: \u0026nbsp;V.1.2, PDX11: V.1.3, PDX12:V.1.2, PDX13:V.1.1-2, PDX16: V.1.2, PDX18: V.1.3, \u0026nbsp;PDX18BIS: V.1.3, and PDX24: V.1.3. N: not available (due to the differences in the panel) White cells: WT sequence C) Representative example of the time to generate the PDX model, demonstrating the time \u0026nbsp;(day) between tumor engraftment until euthanasia of the mouse. \u0026nbsp;P0 : Patient, P1: Passage 1, P2: Passage 2, P3: Passage 3, P4: Passage 4\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/db65d48acdabe22fcd709ecc.png"},{"id":68355129,"identity":"3d48b55e-28ca-4ea2-8c52-cddbdec07239","added_by":"auto","created_at":"2024-11-06 11:14:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95818,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity to azacitidine for TFHL-PDX models and their source patient A) Schematic representation of azacitidine treatment. Tumor cells were implanted into \u0026nbsp;NSG mice and circulating tumor cells were detected after 10 days. The treatment started \u0026nbsp;upon detection of circulating tumor cells and the mice received intraperitoneal injections of 2.5 mg/kg azacitidine every other day for a total of five doses and the cycle was repeated every four weeks until the humane end point. B) The efficacy of 5-azacitidine treatment in different PDX models. Three PDXs (PDX11, \u0026nbsp;PDX12, and PDX18) developed from responsive models and two PDXs (PDX13 and \u0026nbsp;PDX6bis) developed from refractory patients received azacitidine treatment. The \u0026nbsp;weekly percentage of circulating tumor cells, followed during the treatment period, is shown on the first line of the figure. In the second line, the overall survival rate of \u0026nbsp;azacitidine- and placebo-treated mice is shown. T-tests and Log-rank tests were used to \u0026nbsp;determine significance changes in the percentage of circulating tumor cells and mouse survival curves, respectively. \u0026nbsp;C) Schematic representation of the efficacy of azacitidine treatment in PDXs generated \u0026nbsp;from the initial biopsy (PDX18) or relapse biopsy (PDX18bis) of the same patient. \u0026nbsp;Black dots represent placebo-treated mice and red dots azacitidine-treated mice\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/29bfcd3e5f33a245109649ec.png"},{"id":68355356,"identity":"9eb484bc-c9dd-4a53-bc87-33b7ca88ca47","added_by":"auto","created_at":"2024-11-06 11:22:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":135356,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in DNA methylation induced by azacitidine treatment A) Principal component analysis with the 10,000 most variable CpGs. Colors indicate the \u0026nbsp;treatment status or primary tumor sample. Circles highlight the four different TFHL-PDX models. \u0026nbsp;B) Heatmap showing the beta values for the 10,000 most variable CpGs. Hierarchical \u0026nbsp;clustering shows separation between the four different TFHL-PDX models. \u0026nbsp;C) Density plot showing mean DNA methylation for the three sensitive models (PDX11, \u0026nbsp;PDX12, and PDX18) and the resistant model (PDX6bis).\u003c/p\u003e\n\u003cp\u003eD) Median global DNA methylation for the patient tissue group, as well as the placebo and azacitidine-treated TFHL-PDX models. \u0026nbsp;E) The absolute delta beta value was calculated for each PDX model by using triplicates. \u0026nbsp;Each CpG was categorized as \u0026gt; or ≤ 0.1.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/244548221c9d849484d7a7a4.png"},{"id":68355128,"identity":"b7a097fc-52dc-47c7-9f53-b16568ac40b7","added_by":"auto","created_at":"2024-11-06 11:14:31","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":286904,"visible":true,"origin":"","legend":"\u003cp\u003eEffect of azacitidine on HERV and gene expression profiles A) Volcano plots of differentially expressed HERV genes in PDX11, PDX12, PDX18, and \u0026nbsp;PDX6bis for treated versus placebo mice. B) Selected antiviral response gene set enrichment of responsive models (*p-adj \u0026lt; 0.1, **p-adj \u0026lt; 0.05, ***p-adj \u0026lt; 0.01). NES: normalized enrichment score. C) Profile of change in expression of protein-coding genes after azacitidine treatment in \u0026nbsp;sensitive models (PDX11, PDX12, and PDX18). \u0026nbsp;D) Hallmark gene set enrichment of DEGs (i.e. genes with |log2(foldchange)| \u0026gt; 1 and p-value \u0026lt; 0.05) in sensitive models (PDX11, PDX12, and PDX18). The X-axis shows \u0026nbsp;normalized gene enrichment, and the Y-axis shows hallmarks. \u0026nbsp;E) Effect of azacitidine on the p-53 pathway at the protein level by IHC. Positive cells \u0026nbsp;were quantified using Quapath software and normalized to the CD4+ cell count and the \u0026nbsp;placebo.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/1daf945af63f390fadfa6e05.png"},{"id":68356790,"identity":"6ad5e54a-af02-43c6-9183-9ba9f8e851af","added_by":"auto","created_at":"2024-11-06 11:30:34","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":812791,"visible":true,"origin":"","legend":"","description":"","filename":"20240918articlemerged.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1_covered_449dd3ff-807f-4568-8e95-4d1b9db130f7.pdf"},{"id":68355124,"identity":"2def9e54-d8ea-4332-8fa1-6823c5324fb4","added_by":"auto","created_at":"2024-11-06 11:14:31","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11189,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. PDX information 5-aza: azacitidine, BV: brentuximab vedotin, CC200: iberdomide, CC486: oral azacytidine, CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone, CHOP E: CHOP + \u0026nbsp;etoposide, CR: complete response, DHAC: dexamethasone, GEMOX: gemcitabine, oxaliplatin, ICE: ifosfamide, carboplatin, etoposide, NA: not available, PD: progressive disease, SCT, stem \u0026nbsp;cell transplant, SD: stable disease, WT: wildtype\u003c/p\u003e","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/4d6fdf1b70ffa74cb4dec93e.xlsx"},{"id":68355130,"identity":"e527bf50-f085-4447-a9a6-6b6609eda408","added_by":"auto","created_at":"2024-11-06 11:14:31","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":4295767,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Supplementary.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5117296/v1/80a7e12846c3ad86ac2ef0d9.pdf"}],"financialInterests":"\u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e there is potential conflict of interest.\u003c/p\u003e\n\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e","formattedTitle":"Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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-5117296/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5117296/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Follicular helper T-cell lymphoma (TFHL) is the most common non-cutaneous T-cell lymphoma in the Western world and is associated with a poor prognosis. Neoplastic cells rely heavily on the tumor microenvironment, demonstrated by the absence of TFHL-derived cell lines, which hinders therapeutic progress. \r\nTo overcome this limitation, we developed and characterized patient-derived xenograft TFHL (TFHL-PDXs). Fifteen TFHLs were implanted into immunodeficient mice, generating nine PDXs. The tumor microenvironment was detected in the first passage but progressively disappeared in subsequent passages. TET2 mutations persisted in all cases and TFHL-specific mutations were observed in most. The models were treated with azacitidine and patient sensitivity was fully recapitulated. To elucidate the mechanism of action of azacitidine, we analyzed the differences in DNA methylation and gene expression in four TFHL-PDX models. Global DNA hypomethylation occurred in azacitidine-treated cells in drug-sensitive models but not in the resistant one. DNA hypomethylation was associated with global upregulation of gene expression, including that of various cancer-related pathways, suggestive of p53-pathway-mediated cytotoxicity.\r\nOverall, the PDXs recapitulated TFHL features and exhibited sensitivity to azacitidine. They also made it possible to decipher the mechanism responsible for the effect of azacitidine, revealing the activation of p53-mediated apoptosis associated with DNA hypomethylation.","manuscriptTitle":"Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-06 11:14:26","doi":"10.21203/rs.3.rs-5117296/v1","editorialEvents":[{"type":"communityComments","content":0}],"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":"44385209-9e20-4f41-9793-08901fa258c7","owner":[],"postedDate":"November 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":38075711,"name":"Biological sciences/Cancer/Cancer models"},{"id":38075712,"name":"Health sciences/Medical research/Preclinical research"},{"id":38075713,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Lymphoma/Non-hodgkin lymphoma/T-cell lymphoma"}],"tags":[],"updatedAt":"2025-03-25T12:15:52+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-06 11:14:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5117296","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5117296","identity":"rs-5117296","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}