Oncogenic RAS-Pathway Activation Drives Oncofetal Reprogramming and Creates Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia

Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis1. Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins2-6. In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease7-10. To date, OFR has not been described in the context of childhood malignancies. Here, we performed a comprehensive multi-layered molecular characterization of juvenile myelomonocytic leukemia (JMML) and identified OFR as a hallmark of aggressive JMML. We observed that hematopoietic stem cells (HSCs) aberrantly express mixed developmental programs in JMML. Expression of fetal gene signatures combined with a postnatal epigenetic landscape suggested OFR, which was validated in a JMML mouse model, demonstrating that postnatal activation of RAS signaling is sufficient to induce fetal gene signatures. Integrative analysis identified the fetal HSC maturation marker CD52 as a novel therapeutic target for aggressive JMML. Anti-CD52 treatment depleted human JMML HSCs and disrupted disease propagation in vivo. In summary, this study implicates OFR, defined as postnatal acquisition of fetal transcription signatures, in the pathobiology of a childhood malignancy. We provide evidence for the direct involvement of oncogenic RAS signaling in OFR. Finally, we demonstrate how OFR can be leveraged for the development of novel treatment strategies. Highlights{blacksquare} Epigenomic and transcriptomic landscape of juvenile myelomonocytic leukemia (JMML) in the context of hematopoietic development. {blacksquare}The presence of fetal transcription signatures in childhood malignancies is not indicative of a developmental maturation block. {blacksquare}High-risk JMML is characterized by oncofetal reprogramming of postnatal hematopoietic stem cells (HSCs). {blacksquare}RAS-pathway mutations induce fetal-like gene expression signatures in murine postnatal HSCs. {blacksquare}The fetal maturation marker CD52 is a novel therapeutic target in high-risk JMML.