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| Home > Publications database > Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia. |
| Home > Publications database > Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia. |
| Journal Article (Review Article) | DKFZ-2025-02807 |
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2025
American Association for Cancer Research
Philadelphia, PA
Abstract: 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.
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