Work

Intense TP53 pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease

Year: 2026

Type: preprint

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.

Source: medRxiv

DOI: 10.64898/2026.09.16.26363199