Genomic and Epigenomic Landscape of Juvenile Myelomonocytic Leukemia

SIMPLE SUMMARY: Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myelodysplastic/myeloproliferative neoplasm characterized by the constitutive activation of the RAS pathway. In spite of the recent progresses in the molecular characterization of JMML, this disease is still a clinical challenge due to its heterogeneity, difficult diagnosis, poor prognosis, and the lack of curative treatment options other than hematopoietic stem cell transplantation (HSCT). In this review, we will provide a detailed overview of the genetic and epigenetic alterations occurring in JMML, and discuss their clinical relevance in terms of disease prognosis and risk of relapse after HSCT. We will also present the most recent advances on novel preclinical and clinical therapeutic approaches directed against JMML molecular targets. Finally, we will outline future research perspectives to further explore the oncogenic mechanism driving JMML leukemogenesis and progression, with special attention to the application of single-cell next-generation sequencing technologies. ABSTRACT: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm of early childhood. Most of JMML patients experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation, which is currently the only curative treatment. JMML is characterized by RAS signaling hyperactivation, which is mainly driven by mutations in one of five genes of the RAS pathway, including PTPN11, KRAS, NRAS, NF1, and CBL. These driving mutations define different disease subtypes with specific clinico-biological features. Secondary mutations affecting other genes inside and outside the RAS pathway contribute to JMML pathogenesis and are associated with a poorer prognosis. In addition to these genetic alterations, JMML commonly presents aberrant epigenetic profiles that strongly correlate with the clinical outcome of the patients. This observation led to the recent publication of an international JMML stratification consensus, which defines three JMML clinical groups based on DNA methylation status. Although the characterization of the genomic and epigenomic landscapes in JMML has significantly contributed to better understand the molecular mechanisms driving the disease, our knowledge on JMML origin, cell identity, and intratumor and interpatient heterogeneity is still scarce. The application of new single-cell sequencing technologies will be critical to address these questions in the future.