Abstract
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Outcomes in JMML vary markedly from spontaneous resolution to rapid relapse after hematopoietic stem cell transplantation. Here, we hypothesized that DNA methylation patterns would help predict disease outcome and therefore performed genome-wide DNA methylation profiling in a cohort of 39 patients. Unsupervised hierarchical clustering identifies three clusters of patients. Importantly, these clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Notably, all but one of 14 patients experiencing spontaneous resolution cluster together and closer to 22 healthy controls than to other JMML cases. Thus, we show that DNA methylation patterns in JMML are predictive of outcome and can identify the patients most likely to experience spontaneous resolution.
Highlights
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway
SETBP1 is mutated in up to 30% of patients as a secondary event, and we previously showed that subclonal mutations in SETBP1 at diagnosis are associated with poor outcome[7]
Several groups have reported that secondary genetic mutations within and outside of the canonically defined Ras pathway are present in roughly a third of patients and that these mutations are associated with a worse prognosis[4,5,6]
Summary
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder of childhood caused by mutations in the Ras pathway. Unsupervised hierarchical clustering identifies three clusters of patients These clusters differ significantly in terms of 4-year event-free survival, with the lowest methylation cluster having the highest rates of survival. These findings were validated in an independent cohort of 40 patients. Spontaneous resolution of JMML with minimal to no traditional chemotherapy or hematopoietic stem cell transplantation (HSCT) is rare but has been reported[8] This phenomenon is more common in patients with germline syndromes such as Noonan[9] and CBL syndrome[10], it has been seen in a handful of patients with somatic NRAS and KRAS mutations[8] that are typically less than one year of age and have high platelet counts. These data suggest that DNA methylation can be used to predict outcome in JMML
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