TY  - JOUR
AU  - Hartmann, Mark
AU  - Schönung, Maximilian
AU  - Rajak, Jovana
AU  - Maurer, Valentin
AU  - Hai, Ling
AU  - Bauer, Katharina
AU  - Hakobyan, Mariam
AU  - Stäble, Sina
AU  - Langstein, Jens
AU  - Jardine, Laura
AU  - Roelz, Roland
AU  - Bohler, Sheila
AU  - Khabirova, Eleonora
AU  - Maag, Abdul-Habib
AU  - Vonficht, Dominik
AU  - Lebrecht, Dirk
AU  - Bernt, Kathrin M
AU  - Tan, Kai
AU  - Chen, Changya
AU  - Alikarami, Fatemeh
AU  - Meyer, Julia
AU  - Wang, Jun
AU  - Boch, Tobias
AU  - Flore, Nina Viktoria
AU  - Lutsik, Pavlo
AU  - Milsom, Michael
AU  - Raffel, Simon
AU  - Buske, Christian
AU  - Haas, Simon
AU  - Haniffa, Muzlifah
AU  - Mallm, Jan-Philipp
AU  - Behjati, Sam
AU  - Bonder, Marc Jan
AU  - Fröhling, Stefan
AU  - Stieglitz, Elliot
AU  - Niemeyer, Charlotte M
AU  - Hey, Joschka
AU  - Flotho, Christian
AU  - Plass, Christoph
AU  - Erlacher, Miriam
AU  - Schlesner, Matthias
AU  - Lipka, Daniel
TI  - Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.
JO  - Blood cancer discovery
VL  - nn
SN  - 2643-3230
CY  - Philadelphia, PA
PB  - American Association for Cancer Research
M1  - DKFZ-2025-02807
SP  - nn
PY  - 2025
N1  - DKFZ-ZMBH Alliance/  #EA:B340#LA:B340#LA:B370#LA:W610# / epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:41348944
DO  - DOI:10.1158/2643-3230.BCD-25-0246
UR  - https://inrepo02.dkfz.de/record/306830
ER  -