A myelodysplastic/myeloproliferative disease of childhood that is characterized by proliferation principally of the granulocytic and monocytic lineages. Myelomonocytic proliferation is seen in the bone marrow and the blood. The leukemic cells may infiltrate any tissue, however liver, spleen, lymph nodes, skin, and respiratory tract are the most common sites of involvement. The prognosis is usually poor. [From Genetics Home Reference, Glossary, Juvenile myelomonocytic leukemia. 2015.04.16]

Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009, pubmed:19571318). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999, pubmed:10086728). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997, pubmed:9160658). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (MIM:601511) hyperphosphorylation (Loh et al., 2009, pubmed:19571318). [from MIM:607785, 2016.03.29]

Mutations in NF1, NRAS, KRAS, PTPN11, and CBL occur in 85% of patients (Stieglitz et al., 2015; pubmed:26457647).

Juvenile myelomonocytic leukemia (JMML) can be caused by somatic mutations in specific genes that result in activation of the RAS signaling pathway, such as PTPN11, NRAS (MIM:164790), and KRAS (MIM:190070). Somatic mutation in the CBL (MIM:165360) gene has also been reported. [from MIM:607785, 2016.03.29]

In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11, KRAS (MIM:190070), and NRAS (MIM:164790) genes. Additionally, both germline and somatic mutations in the CBL (MIM:165360) gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009, pubmed:19571318). Somatic disruptions of the GRAF gene (ARHGAP26, MIM:605370) have also been found in patients with JMML. About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1, MIM:162200, FBhh0000197) due to germline mutations in the NF1 (MIM:613113) gene. In addition, patients with Noonan syndrome (NS1, MIM:163950, FBhh0000040; NS3, MIM:609942) or Noonan syndrome-like disorder (NSLL, MIM:613563) due to germline mutations in the PTPN11, KRAS, and CBL genes, respectively, also have an increased risk of developing JMML. [from MIM:607785, 2016.03.29]