{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:40Z","timestamp":1792790320527,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,1]]},"group-title":"Genetics","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH Common Fund","award":["R01 AI128589"],"award-info":[{"award-number":["R01 AI128589"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"NIH Common Fund","award":["R35 CA210043"],"award-info":[{"award-number":["R35 CA210043"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Dutch Research Council","award":["09150182210049"],"award-info":[{"award-number":["09150182210049"]}],"id":[{"id":"https:\/\/ror.org\/04jsz6e67","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Dutch Research Council","award":["PharmaNL"],"award-info":[{"award-number":["PharmaNL"]}],"id":[{"id":"https:\/\/ror.org\/04jsz6e67","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the Ten-Eleven Translocation (TET) family of DNA dioxygenases are among the most common epigenetic alterations in clonal hematopoiesis and hematologic malignancies, yet how TET loss of function reshapes genome evolution during cellular expansion remains to be fully understood. Here we show that loss of\n                  <jats:italic>Tet2\/3<\/jats:italic>\n                  in invariant natural killer T (iNKT) cells drives aggressive lymphoid expansion that is consistently associated with recurrent chromosome 17 trisomy, a dominant aneuploid state observed across more than ten independently derived tumors following transplantation into immunocompetent recipient mice. Single-cell whole-genome sequencing of TET-deficient iNKT cells induced to proliferate in culture with antigen and IL-2 stimulation revealed that rare pre-existing cells with chromosome 17 trisomy appeared soon after\n                  <jats:italic>Tet<\/jats:italic>\n                  gene deletion in the thymus, together with cells harboring other copy number alterations, but only the cells with chromosome 17 trisomy were progressively enriched during further expansion. Similarly, inducibly\n                  <jats:italic>Tet<\/jats:italic>\n                  -deficient mouse embryonic stem cells (mESCs) showed selection for aneuploid states that were present prior to\n                  <jats:italic>Tet<\/jats:italic>\n                  gene deletion, including trisomy of chromosome 6. Reanalysis of independent datasets from\n                  <jats:italic>Dnmt3a<\/jats:italic>\n                  -deficient mouse lymphomas identified recurrent chromosome gains, including chromosome 17 trisomy. Our results establish\n                  <jats:italic>TET<\/jats:italic>\n                  and\n                  <jats:italic>DNMT3A<\/jats:italic>\n                  deficiency as drivers of karyotypic evolution, and suggest that disruption of DNA methylation\/ demethylation pathways through either\n                  <jats:italic>TET<\/jats:italic>\n                  or\n                  <jats:italic>DNMT3A<\/jats:italic>\n                  deletion promotes chromosomal instability, in part by facilitating the emergence and selection of cryptic aneuploid subclones during clonal expansion.\n                <\/jats:p>","DOI":"10.64898\/2026.09.27.754858","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:20:11Z","timestamp":1790882411000},"source":"Crossref","is-referenced-by-count":0,"title":["TET loss of function selects for aneuploidies that confer a proliferative advantage"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3720-0722","authenticated-orcid":false,"given":"Isaac F.","family":"L\u00f3pez-Moyado","sequence":"first","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9342-1300","authenticated-orcid":false,"given":"Kazumasa","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3835-4626","authenticated-orcid":false,"given":"Lot","family":"Hern\u00e1ndez-Espinosa","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9084-6218","authenticated-orcid":false,"given":"Dani\u00eblle","family":"Koot","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9891-1897","authenticated-orcid":false,"given":"Ren\u00e9","family":"Wardenaar","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"},{"name":"iPsomics, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0989-3127","authenticated-orcid":false,"given":"Floris","family":"Foijer","sequence":"additional","affiliation":[{"name":"European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands"},{"name":"iPsomics, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1870-1775","authenticated-orcid":false,"given":"Anjana","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037, USA"},{"name":"Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA"},{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, 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