Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia

Seiji Kojima and colleagues report whole-exome sequencing of 13 juvenile myelomonocytic leukemias. They identify RAS pathway mutations in 82 of the 92 total cases analyzed and mutations in SETBP1 or JAK3 in 16 cases. Juvenile myelomonocytic leukemia (JMML) is an intractable pediatric leukemia with poor prognosis 1 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 2 , 3 , 4 . 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.