JMML genomics and decisions

Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):307-312. doi: 10.1182/asheducation-2018.1.307.


Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, CBL), which define genetically and clinically distinct JMML subtypes. Three subtypes, PTPN11- , NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in non syndromic children, while two subtypes, JMML in neurofibromatosis type 1 and in JMML in children with CBL syndrome, are characterized by germ line RAS disease and acquired biallelic inactivation of the respective tumor suppressor genes in hematopoietic cells. In addition to the initiating RAS pathway lesion, secondary genetic alterations within and outside of the RAS pathway are detected in about half the patients. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive of outcome. JMML is a stem cell disorder, and most JMML patients require allogeneic stem cell transplantation for long-term survival. However, spontaneous disease regression is noted in the majority of children with CBL-mutated JMML and in some NRAS-mutated cases. In the absence of 1 of the 5 canonical RAS pathway alteration, rare mutations in other RAS genes and non-JMML myeloproliferative disorders need to be excluded. Understanding the genetic basis of myeloproliferative disorders in early childhood will greatly improve clinical decision making.

Publication types

  • Review

MeSH terms

  • Allografts
  • Child
  • DNA Methylation
  • DNA, Neoplasm / genetics
  • DNA, Neoplasm / metabolism
  • Decision Making*
  • Genome-Wide Association Study
  • Humans
  • Leukemia, Myelomonocytic, Juvenile* / genetics
  • Leukemia, Myelomonocytic, Juvenile* / metabolism
  • Leukemia, Myelomonocytic, Juvenile* / pathology
  • Leukemia, Myelomonocytic, Juvenile* / therapy
  • Mutation
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Signal Transduction
  • Stem Cell Transplantation*


  • DNA, Neoplasm
  • Neoplasm Proteins