{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:19:07Z","timestamp":1785424747357,"version":"3.56.0"},"posted":{"date-parts":[[2025,8,7]]},"group-title":"Cancer Biology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T00:00:00Z","timestamp":1754524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01-CA068939"],"award-info":[{"award-number":["R01-CA068939"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["5T32GM083937"],"award-info":[{"award-number":["5T32GM083937"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>The mutational profile of classic Hodgkin lymphoma (cHL) overlaps with that of related B cell lymphomas, including primary mediastinal B cell lymphoma (PMBL), and yet these are different histologically and clinically. To discover the molecular features that distinguish cHL, we deployed flow cytometric cell sorting and low-input RNA sequencing to generate full transcriptome data from viable, isolated Hodgkin and Red-Sternberg (HRS) cells from eighteen primary tumors, alongside matched intra-tumoral non-neoplastic B cells and four cell lines. Comparison of HRS cells to normal cellular subsets revealed evidence of abortive plasma cell differentiation, with an unfolded protein response signature, shared with plasma cell neoplasms, but not other B-cell lymphoma types. Comparison of cHL to PMBL revealed similarities but also key differences in B cell differentiation programs accompanied by upregulation of genes involved in microtubule cytoskeleton organization in cHL, which may be related to the unique multinucleated nature of HRS cells. In HRS cells, we also observed a downregulation of SLAM family receptors, which are crucial for NK cell activation, providing a potential mechanism for immune evasion from NK-mediated killing.<\/jats:p>\n                <jats:sec>\n                  <jats:title>STATEMENT OF SIGNIFICANCE<\/jats:title>\n                  <jats:p>This study defines a unique transcriptional program in classic Hodgkin Lymphoma (cHL) marked by oncogenic signaling, chromatin integrity, DNA repair, and immune escape including loss of NK-activating receptors. HRS cells resemble plasma cells and have an unfolded protein response signature, which distinguishes them from diffuse large and primary mediastinal B cell lymphomas.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.08.05.667241","type":"posted-content","created":{"date-parts":[[2025,8,7]],"date-time":"2025-08-07T15:05:18Z","timestamp":1754579118000},"source":"Crossref","is-referenced-by-count":0,"title":["Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Sternberg cells reveals escape from NK cell recognition and an unfolded protein response"],"prefix":"10.64898","author":[{"given":"Mikhail","family":"Roshal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella Y","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wikum","family":"Dinalankara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B.","family":"Reichel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Teater","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavneet","family":"Binder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakellarios","family":"Zairis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Brody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita I.","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Kovach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Oberley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan S.","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J","family":"Barth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Elemento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ari","family":"Melnick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7946-9255","authenticated-orcid":false,"given":"Raul","family":"Rabadan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Chadburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7336-8071","authenticated-orcid":false,"given":"Luigi","family":"Marchionni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Giulino-Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethel","family":"Cesarman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025102917551006000_2025.08.05.667241v2.1","unstructured":"Swerdlow SH , Campo E , Harris NL , Jaffe ES , Pileri SA , Stein H , et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France 2008."},{"key":"2025102917551006000_2025.08.05.667241v2.2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200316624"},{"key":"2025102917551006000_2025.08.05.667241v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature09754"},{"key":"2025102917551006000_2025.08.05.667241v2.4","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.12875"},{"key":"2025102917551006000_2025.08.05.667241v2.5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-428896"},{"key":"2025102917551006000_2025.08.05.667241v2.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-439570"},{"key":"2025102917551006000_2025.08.05.667241v2.7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI95993"},{"key":"2025102917551006000_2025.08.05.667241v2.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-11-610436"},{"key":"2025102917551006000_2025.08.05.667241v2.9","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019001012"},{"key":"2025102917551006000_2025.08.05.667241v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-018-0096-6"},{"key":"2025102917551006000_2025.08.05.667241v2.11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01867"},{"key":"2025102917551006000_2025.08.05.667241v2.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06903-x"},{"key":"2025102917551006000_2025.08.05.667241v2.13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-11-812073"},{"key":"2025102917551006000_2025.08.05.667241v2.14","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-22-0128"},{"key":"2025102917551006000_2025.08.05.667241v2.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05072-7"},{"key":"2025102917551006000_2025.08.05.667241v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/35000501"},{"key":"2025102917551006000_2025.08.05.667241v2.17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-07-2947"},{"key":"2025102917551006000_2025.08.05.667241v2.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08679-z"},{"key":"2025102917551006000_2025.08.05.667241v2.19","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001126"},{"key":"2025102917551006000_2025.08.05.667241v2.20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-06-1841"},{"key":"2025102917551006000_2025.08.05.667241v2.21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031074"},{"key":"2025102917551006000_2025.08.05.667241v2.22","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01053"},{"key":"2025102917551006000_2025.08.05.667241v2.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-439570"},{"key":"2025102917551006000_2025.08.05.667241v2.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1312509110"},{"key":"2025102917551006000_2025.08.05.667241v2.25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124629"},{"key":"2025102917551006000_2025.08.05.667241v2.26","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2014.930850"},{"key":"2025102917551006000_2025.08.05.667241v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2023.113718"},{"key":"2025102917551006000_2025.08.05.667241v2.28","doi-asserted-by":"publisher","DOI":"10.3390\/genes10090716"},{"key":"2025102917551006000_2025.08.05.667241v2.29","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.2014644"},{"key":"2025102917551006000_2025.08.05.667241v2.30","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019002067"},{"key":"2025102917551006000_2025.08.05.667241v2.31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-363820"},{"key":"2025102917551006000_2025.08.05.667241v2.32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy284"},{"key":"2025102917551006000_2025.08.05.667241v2.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029632"},{"key":"2025102917551006000_2025.08.05.667241v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0037-9"},{"key":"2025102917551006000_2025.08.05.667241v2.35","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24901"},{"key":"2025102917551006000_2025.08.05.667241v2.36","unstructured":"Rabadan. Rabadan Lab Pandora. https:\/\/rabadan.c2b2.columbia.edu\/software. <github.com\/RabadanLab\/Pandora>."},{"key":"2025102917551006000_2025.08.05.667241v2.37","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-020-6483-6"},{"key":"2025102917551006000_2025.08.05.667241v2.38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.4.1495"},{"issue":"Suppl 1","key":"2025102917551006000_2025.08.05.667241v2.39","first-page":"S74","article-title":"Identifying the precursors of Hodgkin and Reed-Sternberg cells in Hodgkin\u2019s disease: role of the germinal center in B-cell lymphomagenesis","volume":"21","year":"1999","journal-title":"J Acquir Immune Defic Syndr"},{"issue":"4","key":"2025102917551006000_2025.08.05.667241v2.40","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1182\/blood.V95.4.1443.004k55_1443_1450","article-title":"Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription","volume":"95","year":"2000","journal-title":"Blood"},{"key":"2025102917551006000_2025.08.05.667241v2.41","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-10-3949"},{"key":"2025102917551006000_2025.08.05.667241v2.42","doi-asserted-by":"publisher","DOI":"10.1002\/hon.764"},{"issue":"4","key":"2025102917551006000_2025.08.05.667241v2.43","first-page":"467","article-title":"PRDM1\/BLIMP-1 expression in multiple B and T-cell lymphoma","volume":"91","year":"2006","journal-title":"Haematologica"},{"issue":"12","key":"2025102917551006000_2025.08.05.667241v2.44","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.4049\/jimmunol.146.12.4071","article-title":"Germinal center B cells and antibody production in the bone marrow","volume":"146","year":"1991","journal-title":"J Immunol"},{"key":"2025102917551006000_2025.08.05.667241v2.45","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-09-381905"},{"key":"2025102917551006000_2025.08.05.667241v2.46","doi-asserted-by":"publisher","DOI":"10.1097\/01.MP.0000093627.51090.3F"},{"issue":"7","key":"2025102917551006000_2025.08.05.667241v2.47","first-page":"2220","article-title":"Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin\u2019s disease","volume":"92","year":"1998","journal-title":"Blood"},{"key":"2025102917551006000_2025.08.05.667241v2.48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-590570"},{"key":"2025102917551006000_2025.08.05.667241v2.49","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2010.01765.x"},{"key":"2025102917551006000_2025.08.05.667241v2.50","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3348"},{"key":"2025102917551006000_2025.08.05.667241v2.51","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdf047"},{"key":"2025102917551006000_2025.08.05.667241v2.52","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10603"},{"key":"2025102917551006000_2025.08.05.667241v2.53","doi-asserted-by":"publisher","DOI":"10.1080\/10428190500525789"},{"key":"2025102917551006000_2025.08.05.667241v2.54","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22629"},{"key":"2025102917551006000_2025.08.05.667241v2.55","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090528"},{"key":"2025102917551006000_2025.08.05.667241v2.56","doi-asserted-by":"publisher","DOI":"10.1309\/7371XK6F6P7474XX"},{"key":"2025102917551006000_2025.08.05.667241v2.57","doi-asserted-by":"publisher","DOI":"10.3791\/54399"},{"key":"2025102917551006000_2025.08.05.667241v2.58","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1010"},{"key":"2025102917551006000_2025.08.05.667241v2.59","doi-asserted-by":"publisher","DOI":"10.1101\/002824"},{"key":"2025102917551006000_2025.08.05.667241v2.60","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-3-r25"},{"key":"2025102917551006000_2025.08.05.667241v2.61","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2014-15-2-r29"},{"key":"2025102917551006000_2025.08.05.667241v2.62","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2025102917551006000_2025.08.05.667241v2.63","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2025102917551006000_2025.08.05.667241v2.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"2025102917551006000_2025.08.05.667241v2.65","unstructured":"Kolde R. pheatmap: Pretty Heatmaps. R package version 1.0.13. 2025."},{"key":"2025102917551006000_2025.08.05.667241v2.66","doi-asserted-by":"crossref","unstructured":"Wickham H . ggplot2: Elegant Graphics for Data Analysis.: Springer-Verlag, New York; 2016.","DOI":"10.1007\/978-3-319-24277-4_9"},{"key":"2025102917551006000_2025.08.05.667241v2.67","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1990.9999"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.08.05.667241","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:12:30Z","timestamp":1782277950000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.08.05.667241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,7]]},"references-count":67,"URL":"https:\/\/doi.org\/10.1101\/2025.08.05.667241","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41408-026-01502-1","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,8,7]]},"subtype":"preprint"}}