An increase in somatic mutations predicts poorer outcome in juvenile myelomonocytic leukemia (JMML).
Major finding: An increase in somatic mutations predicts poorer outcome in juvenile myelomonocytic leukemia (JMML).
Concept: Concomitant RAS and PRC2 pathway mutations were identified that drive JMML pathogenesis.
Impact: Identification of JMML mutations will allow for patient risk stratification to better guide treatment.
Juvenile myelomonocytic leukemia (JMML) is a rare early childhood myeloproliferative neoplasm initiated by somatic or germline RAS-activating mutations. It has a poor prognosis, and hematopoietic stem cell transplantation (HSCT) is the only curative therapy; however, some patients exhibit highly aggressive JMML and relapse after treatment, underscoring the need for methods to stratify patients based on risk to guide treatment decisions. Stieglitz, Taylor-Weiner, and colleagues used whole-exome and targeted deep sequencing to genomically characterize a total of 100 samples from patients with JMML, including several matched diagnosis and relapse samples. This analysis confirmed previously reported mutations of RAS pathway genes, and identified other RAS pathway mutations, as well as additional mutations in genes involved in JAK–STAT signal transduction, gene transcription, and splicing. Patients with one or fewer somatic mutations at diagnosis had better outcomes than patients with two or more alterations, and the incidence of relapse in patients treated with HSCT was higher in patients with two or more mutations. Consistent with these findings, Caye and colleagues independently confirmed that additional mutations predict a poor outcome, and identified secondary somatic mutations in sporadic and NF1-associated JMML, including gain-of-function mutations in RAC2. Surprisingly, in both studies, a subset of patients was found to have coexisting RAS pathway mutations, which had largely been considered mutually exclusive and were associated with decreased event-free survival. Furthermore, both groups identified mutations in components of the epigenetic regulator polycomb repressive complex 2 (PRC2), which were shown by Caye and colleagues to decrease PRC2 dosage and alter histone H3 modifications. Taken together, these findings indicate that a dose-dependent, cooperative effect of RAS-activating mutations is important in JMML, but that other mutations have major effects on JMML severity, relapse, and survival. This information has prognostic importance in determining patient risk and identifies mutations that should be further investigated for potential targeted JMML therapies.