RAS pathway mutations drive oncofetal reprogramming in hematopoietic stem cells

Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm caused by mutations of the RAS signaling pathway. We recently established DNA methylation epitypes as a prognostic biomarker in JMML. Yet, the functional role of aberrant DNA methylation and its implication in JMML pathogenesis remained elusive. We conducted a multi-modal analysis to investigate the molecular alterations associated with the JMML epitypes. Hematopoietic stem cells (HSCs) from JMML patients revealed fetal-like gene expression and DNA methylation patterns, suggesting a reprogramming of these cells to an oncofetal state. This effect was most prominent in JMML patients assigned to the high methylation epitype. To experimentally verify that RAS pathway mutations can induce oncofetal reprogramming, we established a JMML mouse model that relies on the induction of Ptpn11-E76K mutations in HSCs of juvenile mice. HSCs from Ptpn11-E76K mutant mice exhibited myeloid priming and activation of fetal-like gene expression programs mimicking the signatures observed in human JMML. In conclusion, we demonstrate that RAS pathway mutations are sufficient to induce oncofetal reprogramming in JMML HSCs.

Publication History

Article published online:
12 May 2023