ONLINE FIRST ALERT! Molecular #Plasticity Results in #Oncofetal #Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia https://t.co/tDFwjZH4cK @BCD_AACR @AACR #childhoodcancer #epigenetics #precisiononcology

Now online: Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia https://t.co/lsPJPaJLr3

Here, in this @Cancer_Cell mini-review, we highlight recent advances in understanding oncofetal reprogramming and explore its emerging potential as a biomarker and therapeutic target in cancer research. @FGinhoux https://t.co/Kmq40vqItQ

Just published by Maximilian Schönung, et al. “Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.” https://t.co/vqT8yawdSG

Just published by Daniel B. Lipka, et al. “Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.” https://t.co/vqT8yawdSG @dblipka1

Go and listen to this talk - exciting data, I promise!

@HeyJosch @dblipka1 @DKFZ @NCT_HD Fatemeh Alikarami @MsJuliaMeyer Jun Wang Tobias Boch @ViktoriaFlore @pavlo_lutsik @MilsomMick @SimonRaffel1 Christian Buske @haas_lab @Muzz_Haniffa Jan-Philipp Mallm Sam Behjati Marc-Jan Bonder @StefanFrohling @estieglitz1 Charlotte M. Niemeyer

@HeyJosch @dblipka1 @DKFZ @NCT_HD Jovana Rajak Valentin Maurer Ling Hai Katharina Bauer @MariamHakobya20 @SinaStaeble Jens Langstein @DrLJardine Roland Roelz Sheila Bohler Eleonora Khabirova Abdul-Habib Maag Dominik Vonficht Dirk Lebrecht Katrin M. Bernt @cdktmw Changya Chen

Deep gratitude To my friend and shared first co-author Maximilian Schönung To the last authors @HeyJosch, Christian Flotho, Christoph Plass, Miriam Erlacher, Matthias Schlesner, and especially @dblipka1 To our host institutes @DKFZ & @NCT_HD And to all co-authors:

Multi-omics integration reveals risk-associated gene expression signatures, identifying CD52 as a potential therapeutic target for high-risk JMML. Anti-CD52 treatment depletes JMML stem cells and disrupts disease propagation in a JMML PDX model.

RAS-pathway mutations induce fetal-like gene expression programs in a JMML mouse model, suggesting RAS-driven oncofetal reprogramming in murine JMML stem cells.

Fetal HSC signatures are enriched in patients without detectable JMML driver mutations at birth.

JMML stem cells show transcriptional plasticity, hijacking parts of distinct developmental programs, including fetal HSC marker genes, leading to mosaic-like developmental expression programs. This suggests the reactivation rather than preservation of oncofetal signatures.

The postnatal maturation state of JMML stem cells challenges the universality of the maturation block model in pediatric malignancies.

JMML epitypes are prognostic biomarkers in JMML. Conservation of such disease-specific epigenetic signatures in HSC-like JMML stem cells and downstream immune cells suggests HSCs or early HSPCs as the cells-of-origin in JMML across JMML epitypes.

Epigenomes encode cell type, developmental state, and disease-specific information. DNA methylomes of JMML stem cells reveal: 1. HSC-like cell type signatures 2. A postnatal maturation state 3. Disease-specific epitypes

Fetal HSC signatures are enriched in patients without detectable JMML driver mutations at birth.

JMML stem cells show transcriptional plasticity, hijacking parts of distinct developmental programs, including fetal HSC marker genes, leading to mosaic-like developmental expression programs. This suggests the reactivation rather than preservation of oncofetal signatures.

The postnatal maturation state of JMML stem cells challenges the universality of the maturation block model in pediatric malignancies.

JMML epitypes are prognostic biomarkers in JMML. Conservation of such disease-specific epigenetic signatures in HSC-like JMML stem cells and downstream immune cells suggests HSCs or early HSPCs as the cells-of-origin in JMML across JMML epitypes.