DNA Methylation in Juvenile Myelomonocytic Leukemia and Its Clinical Significance

Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm that develops during infancy and early childhood. Aberrant DNA methylation constitutes an independent risk factor in JMML .

A total of 41 newly diagnosed JMML were enrolled in this study, including 31 males and 11 females from Dec 2013 to Dec 2023 at our single center. Quantification of DNA methylation was performed using an Illumina Infinium MethylationEPIC Beadchip platform (Illumina). Unsupervised hierarchical clustering of the most variable CpG sites across all JMML samples classified three clusters, low methylation (LM), intermediate methylation (IM), and high methylation (HM).

The median age of patients is 34 months (range: 3-144 months). All patients were followed up until 1 June 2024. The median follow-up time was 23months (range: 2-96 months). The median level of HbF was 14.65% (1.2%-76.1%). The median blast percentage in BM, as measured by flow cytometry, was 2.18% (0-11%). Among the samples analyzed, 8 were classified into the LM subgroup, 16 exhibited IM, and 17 showed HM. In the methylation analysis, a total of 15 patients had both peripheral blood and bone marrow samples sent for testing. Interestingly, both sample types from the same patient exhibited consistent results. The methylation level of one case transitioned from LM to HM during relapse. 34.1% of children carried PTPN11 mutation. Patients with PTPN11 mutations tended to be classified into HM(P=0.02). In univariate analysis, children with PTPN11 mutations had a lower probability of overall survival (OS) (84%±7% vs 42%±13%, P<0.001). Patients in HM subgroup were more likely to have a higher blast percentage in BM (4.39% vs 1.2%, P=0.003) and higher level of HbF (49.9% vs 3.1%, P=0.003) at diagnosis compared to those not. Among children who did not undergo HSCT, those in the HM subgroup exhibited a poorer OS compared to those in the IM and LM subgroups (P=0.06). The 2-year OS for children in the HM subgroup was 65%. HSCT significantly improved the OS of children within the HM (89%±10% vs 25%±15%, P=0.002).

Overall, Patients in the HM subgroup exhibited poor overall survival.HSCT can significantly improve the OS of patients in HM subgroup. Peripheral blood and bone marrow samples from the same patients exhibited consistent patterns of methylation grouping.

No relevant conflicts of interest to declare.