Intense TP53 pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease
- 1University of Helsinki, Helsinki, Finland
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.
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BibTeX
@misc{douglas2026intense,
title = {{Intense TP53 pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease}},
author = {S. P. M. Douglas and I. Kaaja and I. I. Ikonen and L. Langohr and J. Koski and M. Hakkarainen and L. Katainen and G. Barbany and E. Hellstrom-Lindberg and K. Jahnukainen and S. Kakko and T. Siitonen and R. Niinimaki and E. Pitkanen and U. Wartiovaara-Kautto and O. Kilpivaara},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.26363199},
url = {https://www.medrxiv.org/content/10.64898/2026.09.16.26363199v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Intense TP53 pathway selection drives clonal evolution from bone marrow failure to leukemia in ERCC6L2 disease
AU - S. P. M. Douglas
AU - I. Kaaja
AU - I. I. Ikonen
AU - L. Langohr
AU - J. Koski
AU - M. Hakkarainen
AU - L. Katainen
AU - G. Barbany
AU - E. Hellstrom-Lindberg
AU - K. Jahnukainen
AU - S. Kakko
AU - T. Siitonen
AU - R. Niinimaki
AU - E. Pitkanen
AU - U. Wartiovaara-Kautto
AU - O. Kilpivaara
PY - 2026
DA - 2026/09/16
PB - medRxiv
DO - 10.64898/2026.09.16.26363199
UR - https://www.medrxiv.org/content/10.64898/2026.09.16.26363199v1
AB - 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.
ER -