Flore, V. | Search bioRxiv

bioRxiv2026

Dormancy, not apoptosis, restricts hematopoietic stem cell mutagenesis during aging

Genome instability and mutagenesis are hallmarks of aging, acting as drivers of some age-associated pathologies, including cancer1-3. Somatic cells engage multiple layers of protection against mutagenesis, including detoxification of genotoxic metabolites; repair of DNA damage; and elimination of cells which suffer excessive damage4-7. In this context, the intrinsic apoptotic pathway is engaged in response to activation of the DNA damage response (DDR) and is thought to play a major role in limiting accumulation of mutations, particularly in cells that act as an origin for cancer, such as somatic stem cells8,9. However, the dissection of the relative contribution of different protective mechanisms that restrict mutagenesis in such cells is confounded by the long time frame of experiments; relatively low mutation burden in non-malignant cells; and high variance across individuals due to differences in germ line and environment. Here we employ deep whole-genome sequencing (WGS) combined with extended time-course sampling from a range of experimental mouse models to study mutation acquisition in hematopoietic stem cells (HSCs) during aging. Having validated that murine HSCs recapitulate mutation acquisition patterns observed in aged human HSCs, we made the surprising discovery that apoptosis has a negligible role in restricting mutagenesis. Instead, we found that HSC dormancy inhibits mutagenesis during normal aging, with dormant HSCs from old mice demonstrating a mutation burden akin to their young counterparts. Importantly, breaking HSC dormancy via induction of sterile inflammation led to a dramatic acceleration in mutation rate, demonstrating that non-genotoxic environmental stimuli can modulate genome stability. These findings provide new insights into the correlation between inflammation and both aging and carcinogenesis.

cell biology↗

bioRxiv2023

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.

cancer biology↗