{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:00Z","timestamp":1792790400716,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,17]]},"group-title":"Hematology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Research Council of Finland","award":["349760"],"award-info":[{"award-number":["349760"]}],"id":[{"id":"https:\/\/ror.org\/05k73zm37","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Research Council of Finland","award":["322675"],"award-info":[{"award-number":["322675"]}],"id":[{"id":"https:\/\/ror.org\/05k73zm37","id-type":"ROR","asserted-by":"crossref"}]},{"name":"iCAN Digital Precision Cancer Medicine Flagship"},{"id":[{"id":"https:\/\/ror.org\/00ckakm23","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Cancer Foundation Finland","id":[{"id":"https:\/\/ror.org\/0113k5861","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Children&#8242;s Cancer Foundation AAMU","id":[{"id":"https:\/\/ror.org\/009yhf078","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Finnish Special governmental grant for health sciences and research"},{"name":"Incyte Biosciences"},{"id":[{"id":"https:\/\/ror.org\/027xav248","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/02w907m39","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Doctoral Programme for Biomedicine"},{"name":"Biomedicum Helsinki Foundation"},{"id":[{"id":"https:\/\/ror.org\/03bj5da63","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/005rt3g54","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03arxxe13","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/048e7gn38","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/0269hs475","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Finnish Hematology Association"},{"name":"Blood Disease Research Foundation","id":[{"id":"https:\/\/ror.org\/03we23r72","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Orion Research Foundation sr"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,17]]},"abstract":"<jats:p>ERCC6L2 disease (ED) is an inherited bone marrow failure (BMF) syndrome that progresses almost exclusively to erythroid, TP53-mutated myeloid malignancy, but the somatic evolution underlying the progression in patients is unknown. We characterized the genetic landscape of 29 ED patients with longitudinal sampling, integrating whole-genome and single-cell RNA sequencing, and compared the findings with Shwachman-Diamond syndrome (SDS), another TP53 mutation-prone disease, to define somatic evolution across disease stages. ED was defined by early, intense, and recurrent selection of TP53-mutant clones: TP53 mutations were more frequent, more often multiple, and showed steeper age-related expansion than in SDS; all TP53-negative ED patients were children. The burden of multiple TP53 mutations exceeded that of sporadic TP53-mutated myeloid neoplasia and was evident before malignancy. Missense mutations dominated the BMF phase, whereas non-missense mutations were seen in patients with malignancy, consistent with biallelic second hits, marking a stage-dependent shift in p53 inactivation. Beyond TP53, the landscape was strikingly restricted, with PPM1D as the only recurrent driver gene. Notably, despite the DNA-repair function of ERCC6L2, no ED-specific mutational signature emerged; but instead reflected age-associated processes. Malignant progression was accompanied by a complex karyotype, recurrent chromosome 5, 7, and 12p losses enriched in erythroid progenitors, and kataegis, consistent with branched, erythroid-predominant clonal evolution. Our findings establish ED as a paradigm of preleukemic dependency on p53-pathway attenuation. As progression is driven predominantly by p53 and captured longitudinally from the earliest clones, ED offers a model of how TP53-mutated leukemia arises and evolves, with relevance beyond a rare syndrome.<\/jats:p>","DOI":"10.64898\/2026.09.16.26363199","type":"posted-content","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:25:19Z","timestamp":1789712719000},"source":"Crossref","is-referenced-by-count":0,"title":["Intense\n                  <i>TP53<\/i>\n                  pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4412-688X","authenticated-orcid":false,"given":"Suvi P.M.","family":"Douglas","sequence":"first","affiliation":[{"name":"University of Helsinki, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0415-8679","authenticated-orcid":false,"given":"Ilse","family":"Kaaja","sequence":"additional","affiliation":[{"name":"University of Helsinki, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1705-8769","authenticated-orcid":false,"given":"Ina I","family":"Ikonen","sequence":"additional","affiliation":[{"name":"University of Helsinki, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0493-5551","authenticated-orcid":false,"given":"Laura","family":"Langohr","sequence":"additional","affiliation":[{"name":"University of Helsinki, Helsinki, 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Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1449-756X","authenticated-orcid":false,"given":"Timo","family":"Siitonen","sequence":"additional","affiliation":[{"name":"Oulu University Hospital and University of Oulu, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0190-5664","authenticated-orcid":false,"given":"Riitta","family":"Niinimaki","sequence":"additional","affiliation":[{"name":"Oulu University Hospital and University of Oulu, Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9818-6370","authenticated-orcid":false,"given":"Esa","family":"Pitkanen","sequence":"additional","affiliation":[{"name":"University of Helsinki, Helsinki, 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