ONLINE FIRST ALERT! Molecular #Plasticity Results in #Oncofetal #Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia aacrjournals.org/bloodcancerd... @aacrjournals.bsky.social #childhoodcancer #epigenetics #precisiononcology

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

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.

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

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.

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

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.

Deep gratitude to my friend and shared first co-author Maximilian Schönung the last authors @joschkah.bsky.social, Christian Flotho, Christoph Plass, Miriam Erlacher, Matthias Schlesner, and especially @dblipka.bsky.social

Fantastic environment at our host institutes @dkfz.bsky.social & @nct-heidelberg.bsky.social Thanks to all co-authors of this publication: