Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma

Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma | 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 Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma Vasiliki Leventaki, Timothy Shaw, Stanley Pounds, Xueyuan Cao, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4145750/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Nov, 2024 Read the published version in Leukemia → Version 1 posted 9 You are reading this latest preprint version Abstract Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for for 10–15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL(ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA-sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by diferential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK- high group, which had more frequent copy number changes, and was enriched with pathways associated with cell growth, proliferation, metabolic pathways, and. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers Biological sciences/Cancer/Haematological cancer/Lymphoma/Non-hodgkin lymphoma/T-cell lymphoma Biological sciences/Genetics/Cancer genomics Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files ALCLSupplTablev1720231201.xlsx ALCLSupplementalFigures2032024.pdf Cite Share Download PDF Status: Published Journal Publication published 26 Nov, 2024 Read the published version in Leukemia → Version 1 posted Editorial decision: revise 25 Apr, 2024 Review # 2 received at journal 23 Apr, 2024 Reviewer # 2 agreed at journal 06 Apr, 2024 Review # 1 received at journal 26 Mar, 2024 Reviewer # 1 agreed at journal 23 Mar, 2024 Reviewers invited by journal 23 Mar, 2024 Editor assigned by journal 22 Mar, 2024 Submission checks completed at journal 22 Mar, 2024 First submitted to journal 21 Mar, 2024 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-4145750","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":283057501,"identity":"af6f0d1c-0fea-482b-9665-7b5c3425c912","order_by":0,"name":"Vasiliki 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States","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Sandlund","suffix":""},{"id":283057518,"identity":"01b83e60-bb60-4120-87f4-7b9197e19dd7","order_by":17,"name":"Jinghui Zhang","email":"","orcid":"https://orcid.org/0000-0003-3350-9682","institution":"St. Jude Children's Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinghui","middleName":"","lastName":"Zhang","suffix":""},{"id":283057519,"identity":"19be629d-b00b-452d-8767-a4a83956648e","order_by":18,"name":"Charles Mullighan","email":"","orcid":"https://orcid.org/0000-0002-1871-1850","institution":"St Jude Children's Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Charles","middleName":"","lastName":"Mullighan","suffix":""},{"id":283057520,"identity":"7b8870d4-321f-47e2-9e6c-be573fa99991","order_by":19,"name":"Megan Lim","email":"","orcid":"","institution":"Memorial Sloan Kettering Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Megan","middleName":"","lastName":"Lim","suffix":""}],"badges":[],"createdAt":"2024-03-21 21:00:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4145750/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4145750/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41375-024-02468-4","type":"published","date":"2024-11-26T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53659884,"identity":"c99292df-be46-4e6e-b96b-d1b9c9c08c58","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":169899,"visible":true,"origin":"","legend":"\u003cp\u003eGenomic alterations in pediatric ALCL. Heatmap demonstrates the somatic mutation profile and copy number (CN) alterations identified in the cohort of pediatric ALK+ALCL samples by WES, separated by gene functional groups. Only genetic alterations with presumed functional consequences are shown. Split cell for the PRDM1 gene indicates more than one mutation. (*) indicates mutations validated by targeted sequencing or RNAseq.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/ce368ed6e6f3bec0bb974fb0.png"},{"id":53659885,"identity":"d6b5f4d7-b296-4483-a264-e1d196d6b55c","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":272554,"visible":true,"origin":"","legend":"\u003cp\u003eGene expression profile classifies pediatric ALCL into two groups. (A) Unsupervised hierarchical clustering reveals two distinct groups. The top 100 differentially expressed genes are shown as a heatmap. (B) Boxplot of differential ALK expression levels in ALCL samples detected by RNA seq analysis (P=0.026). FPKM, fragments per kilobase of exon per million mapped fragments. (C and D) Pathway analysis in ALK-low and ALK-high groups (KEGG and MSigDB), p-value \u0026lt;0.05 and FDR \u0026lt; 0.05. (E) Differential expression represented as a volcano plot. ALK-low group shows up-regulation of cytokine and immune related markers. ALK-high group shows up-regulation of ALK, MYC, and other proliferative markers. (F) xCell analysis shows differential Immune Scores in ALCL samples.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/1bd563d2ad74dc61ac6df6c1.png"},{"id":53659887,"identity":"c7486c18-9c71-4030-97e1-562a7ce1d83d","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":221290,"visible":true,"origin":"","legend":"\u003cp\u003eGenome-wide DNA methylation classifies pediatric ALCL in two groups. (A) Unsupervised clustering with bootstrapping identified two separate clusters. Each probe was then summarized to a single value for each associated genomic region. Each methylation value was annotated as Hyper-methylation or Hypo-methylation. Differential methylation was performed using Wilcoxon rank-sum test. FPKM, fragments per kilobase of exon per million mapped fragments. (B) Sankey diagram representation of the unsupervised hierarchical clustering result. The diagram depicts the group clustering based on RNA expression and methylation profiling. (C) Histogram of the methylation probe intensity (Beta value) in the ALK-high and ALK-low group (D) Bar plot representation of the differentially methylated gene regions. Hyper-methylated regions were more frequently differentially methylated than hypo-methylated regions. DMP, differentially methylated positions; TSS, transcription start site.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/58e8e41fce3ebaa6ee865a70.png"},{"id":53659889,"identity":"de9ce434-6fd9-481e-8b01-22acdeead723","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":26386,"visible":true,"origin":"","legend":"\u003cp\u003eGenes that show correlation between probe methylation status and ALK expression Correlation analysis is based on Spearman Rank with positive correlation shown in (A) and negative correlation shown in (B). Both are filtered based on an absolute rho value cutoff of 0.75. Bar plots show enriched pathways from EnrichR’s ChEA_2016 sorted by their log transformed p-value score.\u003c/p\u003e","description":"","filename":"Slide4.png","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/a59517e012b9cbd17376edaf.png"},{"id":53659886,"identity":"c6d66cc7-5e98-43bc-90a7-a769f38cf1a1","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":168707,"visible":true,"origin":"","legend":"\u003cp\u003eRelapsed signature score in pediatric ALK+ALCL patients. (A) Differential gene expression analysis between relapse and diagnosis samples from ALCL patients. Genes differentially up-regulated in relapsed samples are highlighted in green. (B) The relapse signature score is calculated based on single-sample GSEA. Samples were ordered based on the calculated relapse signature score. Relapse samples are colored in red. Diagnosis samples of patients who eventually relapse are colored in blue. The remaining diagnosis samples are colored in gray. The median cutoff for the diagnosis samples is indicated by the arrow. (C) Kaplan-Meier graph showing progression free survival (PFS) according to the relapse signature score. The relapse signature score was categorized into HIGH and LOW based on the median level. A statistically significant difference of the Kaplan–Meier survival curves between the high and low malignancy-risk groups was determined by the two-sided log-rank test. The number of patients at risk is listed below the survival curves.\u003c/p\u003e","description":"","filename":"Slide5.png","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/d18f51a7fc601f292f744a9c.png"},{"id":53659888,"identity":"fb929b44-e116-4808-9979-43087763b7b1","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":178760,"visible":true,"origin":"","legend":"\u003cp\u003eOverview of clinical findings and copy number changes associated with the two ALCL groups and impact on outcome. (A) Heatmap with the distribution of clinical findings and copy number alterations in the diagnostic ALCL samples; cases are assigned to ALK-low and ALK-high group based on the expression and methylation profile. Five cases were classified differently based on RNA expression and DNA methylation analysis (designated as unclassifiable) (B) Kaplan-Meier curve showing progression free survival (PFS) in ALCL according to the presence of copy number changes.\u003c/p\u003e","description":"","filename":"Slide6.png","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/0ead00ae9f1fa2654f313a6c.png"},{"id":69981953,"identity":"dfe48452-ea22-4f7d-8f7d-bc5cec5e226e","added_by":"auto","created_at":"2024-11-27 08:05:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1146536,"visible":true,"origin":"","legend":"","description":"","filename":"ALCLgenomicsManuscript032024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1_covered_3cb77ae8-35eb-4ecd-a1d2-0f762fa0c075.pdf"},{"id":53659891,"identity":"514e9009-a9a2-44d7-85fc-c381a83dccb4","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8010881,"visible":true,"origin":"","legend":"","description":"","filename":"ALCLSupplTablev1720231201.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/e2d4c8f22a748a399bd9c79a.xlsx"},{"id":53659890,"identity":"8cb99bc9-1283-4096-8d7d-68dac7ca8e8e","added_by":"auto","created_at":"2024-03-28 16:04:57","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1836666,"visible":true,"origin":"","legend":"","description":"","filename":"ALCLSupplementalFigures2032024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4145750/v1/e3418d9b14f31bb002c0dee4.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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-4145750/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4145750/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for for 10–15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL(ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA-sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by diferential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK- high group, which had more frequent copy number changes, and was enriched with pathways associated with cell growth, proliferation, metabolic pathways, and. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers","manuscriptTitle":"Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-28 16:04:52","doi":"10.21203/rs.3.rs-4145750/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-04-25T11:29:13+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-04-24T02:57:35+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-04-07T02:44:04+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-03-26T13:33:27+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-03-23T22:53:42+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-03-23T16:13:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-22T11:52:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-22T11:51:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"Leukemia","date":"2024-03-21T20:58:53+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":"a39c8f21-98a5-4260-878d-191afd800861","owner":[],"postedDate":"March 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29803169,"name":"Biological sciences/Cancer/Haematological cancer/Lymphoma/Non-hodgkin lymphoma/T-cell lymphoma"},{"id":29803170,"name":"Biological sciences/Genetics/Cancer genomics"}],"tags":[],"updatedAt":"2024-11-27T08:05:19+00:00","versionOfRecord":{"articleIdentity":"rs-4145750","link":"https://doi.org/10.1038/s41375-024-02468-4","journal":{"identity":"leukemia","isVorOnly":false,"title":"Leukemia"},"publishedOn":"2024-11-26 05:00:00","publishedOnDateReadable":"November 26th, 2024"},"versionCreatedAt":"2024-03-28 16:04:52","video":"","vorDoi":"10.1038/s41375-024-02468-4","vorDoiUrl":"https://doi.org/10.1038/s41375-024-02468-4","workflowStages":[]},"version":"v1","identity":"rs-4145750","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4145750","identity":"rs-4145750","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}