%0 Journal Article
%A Hartmann, Mark
%A Schönung, Maximilian
%A Rajak, Jovana
%A Maurer, Valentin
%A Hai, Ling
%A Bauer, Katharina
%A Hakobyan, Mariam
%A Stäble, Sina
%A Langstein, Jens
%A Jardine, Laura
%A Roelz, Roland
%A Bohler, Sheila
%A Khabirova, Eleonora
%A Maag, Abdul-Habib
%A Vonficht, Dominik
%A Lebrecht, Dirk
%A Bernt, Kathrin M
%A Tan, Kai
%A Chen, Changya
%A Alikarami, Fatemeh
%A Meyer, Julia
%A Wang, Jun
%A Boch, Tobias
%A Flore, Nina Viktoria
%A Lutsik, Pavlo
%A Milsom, Michael
%A Raffel, Simon
%A Buske, Christian
%A Haas, Simon
%A Haniffa, Muzlifah
%A Mallm, Jan-Philipp
%A Behjati, Sam
%A Bonder, Marc Jan
%A Fröhling, Stefan
%A Stieglitz, Elliot
%A Niemeyer, Charlotte M
%A Hey, Joschka
%A Flotho, Christian
%A Plass, Christoph
%A Erlacher, Miriam
%A Schlesner, Matthias
%A Lipka, Daniel
%T Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.
%J Blood cancer discovery
%V nn
%@ 2643-3230
%C Philadelphia, PA
%I American Association for Cancer Research
%M DKFZ-2025-02807
%P nn
%D 2025
%Z DKFZ-ZMBH Alliance/  #EA:B340#LA:B340#LA:B370#LA:W610# / epub
%X Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, post-natal activation of oncogenic signaling by inducible Ptpn11E76K mutation in mice, triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation-block model of pediatric leukemogenesis and establish RAS-associated stem-cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41348944
%R 10.1158/2643-3230.BCD-25-0246
%U https://inrepo02.dkfz.de/record/306830