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Lookup NU author(s): Professor Muzlifah Haniffa
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©2025 American Association for Cancer Research. 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, postnatal 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. SIGNIFICANCE: Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic PTPN11 mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities. See related commentary by Miao and Xu, pp. 168.
Author(s): Hartmann M, Schonung M, Rajak J, Maurer V, Hai L, Bauer K, Hakobyan M, Stable S, Langstein J, Jardine L, Roelz R, Bohler S, Khabirova E, Maag A-H, Vonficht D, Lebrecht D, Bernt KM, Tan K, Chen C, Alikarami F, Meyer J, Wang J, Boch T, Flore V, Lutsik P, Milsom MD, Raffel S, Buske C, Haas S, Haniffa M, Mallm J-P, Behjati S, Bonder M-J, Frohling S, Stieglitz E, Niemeyer CM, Hey J, Flotho C, Plass C, Erlacher M, Schlesner M, Lipka DB
Publication type: Article
Publication status: Published
Journal: Blood Cancer Discovery
Year: 2026
Volume: 7
Issue: 2
Pages: 306-330
Print publication date: 01/03/2026
Online publication date: 04/03/2026
Acceptance date: 05/12/2025
ISSN (print): 2643-3230
ISSN (electronic): 2643-3249
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/2643-3230.BCD-25-0246
DOI: 10.1158/2643-3230.BCD-25-0246
PubMed id: 41348944
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