Juvenile myelomonocytic leukemia - A bona fide RASopathy syndrome

Area of Science:

• Pediatric Hematology Oncology
• Cancer Genomics
• Myeloid Neoplasms

Background:

• Juvenile myelomonocytic leukemia (JMML) is a pediatric myelodysplastic/myeloproliferative neoplasm with aggressive features and poor prognosis.
• JMML is characterized by sustained peripheral blood monocytosis.
• Over 90% of JMML cases are driven by germline or somatic mutations in the RAS pathway.

Purpose of the Study:

• To summarize the key molecular drivers and clinical characteristics of JMML.
• To differentiate JMML from its adult counterpart, proliferative chronic myelomonocytic leukemia (pCMML).
• To highlight current therapeutic strategies and the potential for spontaneous regression in specific JMML subtypes.

Main Methods:

• Review of existing literature on JMML.
• Analysis of genetic mutations commonly found in JMML, including RAS pathway genes, SETBP1, ASXL1, and JAK3.
• Comparison of JMML pathogenesis with age-related clonal hematopoiesis in pCMML.

Main Results:

• JMML is primarily driven by RAS pathway mutations (PTPN11, NRAS, CBL, KRAS, NF1), often with a secondary hit.
• Somatic mutations in SETBP1, ASXL1, and JAK3 contribute to disease progression.
• Spontaneous regression occurs in some JMML cases with germline PTPN11 and CBL mutations.
• JMML is a RASopathy with additional mutations in epigenetic regulators, contrasting with pCMML's drivers (TET2, SRSF2, ASXL1).

Conclusions:

• JMML pathogenesis involves RAS pathway mutations and additional genetic alterations.
• Allogeneic stem cell transplant is the main curative option for most JMML patients.
• Understanding JMML's distinct molecular landscape from pCMML is crucial for targeted therapies.