Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Nat Genet. 2013 Aug;45(8):937-41. doi: 10.1038/ng.2698. Epub 2013 Jul 7.
Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis whose molecular pathogenesis is poorly understood, except for somatic or germline mutations of RAS pathway genes, including PTPN11, NF1, NRAS, KRAS and CBL, in the majority of cases. To obtain a complete registry of gene mutations in JMML, whole-exome sequencing was performed for paired tumor-normal DNA from 13 individuals with JMML (cases), which was followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 non-silent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 genes were among common targets for secondary mutations. Mutations in the latter were often subclonal and may be involved in the progression rather than the initiation of leukemia, and these mutations associated with poor clinical outcome. Our findings provide new insights into the pathogenesis and progression of JMML.
儿童骨髓单核细胞白血病（JMML）是一种预后不良的难治性小儿白血病，其分子发病机制除了在大多数情况下存在 RAS 通路基因（包括 PTPN11、NF1、NRAS、KRAS 和 CBL）的体细胞或种系突变外，其他了解甚少。为了获得 JMML 基因突变的完整登记，对 13 例 JMML（病例）的肿瘤-正常 DNA 进行了全外显子组测序，随后对 92 个肿瘤样本中的 8 个靶基因进行了深度测序。JMML 的特点是基因突变很少（每个样本 0.85 个非沉默突变），82 例（89%）存在体细胞或种系 RAS 通路参与。SETBP1 和 JAK3 基因是常见的继发突变靶标。后者的突变通常是亚克隆的，可能参与白血病的进展而不是起始，这些突变与不良的临床结果相关。我们的发现为 JMML 的发病机制和进展提供了新的见解。
