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Data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007357. Further information about EGA can be found at https://ega-archive.org and "The European Genome-phenome Archive of human data consented for biomedical research"

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Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia

Aberrant fetal gene expression in cancer is considered to facilitate tumor-specific cellular plasticity by hijacking features of embryogenesis, inflammation, and immunosuppression. In early childhood cancers, prenatal origins might explain preserved fetal gene signatures. In adult malignancies, the reactivation of fetal-like gene expression profiles is considered as a consequence of onco-fetal reprogramming (OFR). Although this phenomenon is often associated with aggressive disease and poor outcome, underlying molecular mechanisms remain elusive. Furthermore, the role of OFR in childhood malignancies is subject to speculation. In the present study we demonstrate that an aggressive form of childhood cancer, high-risk juvenile myelomonocytic leukemia (JMML), is characterized by OFR in hematopoietic stem cells (HSC) that is directly driven by oncogenic RAS signaling. Single-cell transcriptome and low-input DNA methylome analyses of JMML patient samples revealed widespread epigenomic and transcriptomic aberrations, which provided evidence that the disease-initiating cells reside within the HSC compartment. In depth analysis of JMML HSCs revealed complex disease- and subtype-specific patterns characterized by fetal-like expression signatures combined with a predominantly postnatal epigenetic landscape, suggesting onco-fetal reprogramming. To experimentally test this, we employed a JMML mouse model in which we demonstrated that postnatal activation of RAS signaling is sufficient to induce fetal-like molecular signatures in HSCs. In patients, onco-fetal reprogramming triggers variegated developmental programs, leading to altered priming, immune activation, and chronic inflammation of high-risk HSCs. Multi-omics analysis of JMML stem cells identified several epitype-specific surface proteins as novel biomarkers for high-risk JMML. Among those factors was CD52, which has previously been described as a fetal stem cell marker. Immunotherapeutic targeting of CD52 led to reduced leukemic engraftment and increased survival in a patient-derived xenograft mouse model, providing a preclinical rationale for further assessment of a CD52-targeted treatment of high-risk JMML. This study implicates oncogenic RAS signaling in the process of onco-fetal reprogramming and demonstrates how aberrantly expressed genes can be identified and leveraged for risk-stratification and the development of novel treatment strategies, as exemplified by an anti-CD52 treatment.

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