{
  "abstract": "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Helsinki, Helsinki, Finland"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "S. P. M. Douglas"
    },
    {
      "name": "I. Kaaja"
    },
    {
      "name": "I. I. Ikonen"
    },
    {
      "name": "L. Langohr"
    },
    {
      "name": "J. Koski"
    },
    {
      "name": "M. Hakkarainen"
    },
    {
      "name": "L. Katainen"
    },
    {
      "name": "G. Barbany"
    },
    {
      "name": "E. Hellstrom-Lindberg"
    },
    {
      "name": "K. Jahnukainen"
    },
    {
      "name": "S. Kakko"
    },
    {
      "name": "T. Siitonen"
    },
    {
      "name": "R. Niinimaki"
    },
    {
      "name": "E. Pitkanen"
    },
    {
      "name": "U. Wartiovaara-Kautto"
    },
    {
      "affs": [
        0
      ],
      "name": "O. Kilpivaara"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fwbt6en5q27r7.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.16.26363199",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363199v1.full",
  "id": "fwbt6en5q27r7",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363199v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "hematology"
    ],
    [
      "openalex",
      "2720|Acute Myeloid Leukemia Research"
    ]
  ],
  "openalex": "W7213547147",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363199v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fwbt6en5q27r7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:49Z",
      "native_id": "10.64898/2026.09.16.26363199",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.16.26363199v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:hematology",
      "subfield": "general"
    }
  ],
  "title": "Intense TP53 pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease",
  "title_text": "Intense TP53 pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:49Z",
  "url": "https://research.draconitic.com/paper/fwbt6en5q27r7",
  "venue": "medRxiv",
  "versions": []
}