Regulation of Cellular Differentiation Group, Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), INF 280, 69120, Heidelberg, Germany.
Department of Hematology and Oncology, Medical Center, Otto-von-Guericke-University, Leipziger Strasse 44, 39120, Magdeburg, Germany.
Nat Commun. 2017 Dec 19;8(1):2126. doi: 10.1038/s41467-017-02177-w.
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.
儿童早发性骨髓单核细胞白血病（JMML）是一种侵袭性骨髓增生性疾病，其特征是激活 RAS 信号的突变。既定的临床和遗传标志物未能充分再现该疾病的临床和生物学异质性。在这里，我们报告了对 167 例 JMML 样本的 DNA 甲基化组分析和突变分析。我们确定了具有独特分子和临床特征的三个 JMML 亚组。高甲基化组（HM）的特征是体细胞 PTPN11 突变和不良的临床结果。低甲基化组富含体细胞 NRAS 和 CBL 突变，以及努南患者，并且预后良好。中间甲基化组（IM）表现出 7 号单体和体细胞 KRAS 突变的富集。高甲基化与抑制性染色质、受 RAS 信号调节的基因、RAS 通路突变的频繁共发生以及 DNMT1 和 DNMT3B 的上调有关，这表明 DNA 甲基化机制的激活与 JMML 中的突变模式之间存在联系。
