Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

Gene mutations do not operate in a vacuum: the increasing importance of epigenetics in juvenile myelomonocytic leukemia

“…It appears that the presence of additional gene mutations is linked to unfavorable outcome [33,37,41]. Deletions of chromosome 7 or part of the 7 q arm are observed in 25% of all cases [1,42] but up to 50% of cases with KRAS mutation [43]. Although monosomy 7/del 7 q is by no means specific to JMML and frequently found in a spectrum of myeloid neoplasms, the significance of this aberration remains poorly understood particularly in JMML [44].…”

“…JMML with somatic PTPN11 mutation is rapidly progressive and requires allogeneic hematopoietic stem cell transplantation (HSCT) for long-term survival [45]. There is a correlation between presence of somatic PTPN11 mutation and other adverse prognostic features such as age or elevated level of fetal hemoglobin [43,46]. JMML in patients with NF-1 is characterized by older age at diagnosis, high platelet count and low frequency of karyotype abnormalities [1].…”

“…With the advent of technology permitting the genome-wide analysis of CpG methylation three large-scale epigenetic analyses in a total of 312 children with JMML or related myeloproliferative disorders were conducted by investigators in Europe, North America, and Japan [43,70,71]. Confirming and extending the conclusions derived from the preceding candidate gene studies, the EWOG-MDS demonstrated in a cohort of 167 cases that JMML can be subdivided in three characteristic categories with low, intermediate, and high DNA methylation, with the methylation differences being most pronounced in or near CpG islands [43].…”

“…With the advent of technology permitting the genome-wide analysis of CpG methylation three large-scale epigenetic analyses in a total of 312 children with JMML or related myeloproliferative disorders were conducted by investigators in Europe, North America, and Japan [43,70,71]. Confirming and extending the conclusions derived from the preceding candidate gene studies, the EWOG-MDS demonstrated in a cohort of 167 cases that JMML can be subdivided in three characteristic categories with low, intermediate, and high DNA methylation, with the methylation differences being most pronounced in or near CpG islands [43]. Each category was associated with distinct clinical and molecular features (Figure 1): the low-methylation group consisted of cases with good prognosis including infants with NRAS mutation, children with Noonan syndrome, or patients with CBL mutation; the intermediate-methylation group had a strong correlation with KRAS mutation and monosomy 7; and the high-methylation group involved cases with poor prognosis and aggressive course such as older children and/or patients with PTPN11 mutation.…”

“…The top section displays color-coded maps of methylation values for 1,000 selected CpG dinucleotides (rows) in leukemia cell samples from a total of 147 patients (columns). The three methylation groups differ in the distribution of Ras pathway mutations, enrichment of cases with monosomy 7, frequency of concomitant mutations, age at diagnosis, and probability of relapse after allogeneic hematopoietic stem cell transplantation (modified from Lipka et al [43]). methylation cluster.…”