title: RAS diseases in children.
abstract: RAS genes encode a family of 21 kDa proteins that are an essential hub for a number of survival, proliferation, differentiation and senescence pathways. Signaling of the RAS-GTPases through the RAF-MEK-ERK pathway, the first identified mitogen-associated protein kinase (MAPK) cascade is essential in development. A group of genetic syndromes, named "RASopathies", had been identified which are caused by heterozygosity for germline mutations in genes that encode protein components of the RAS/MAPK pathway. Several of these clinically overlapping disorders, including Noonan syndrome, Noonan-like CBL syndrome, Costello syndrome, cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, and Legius syndrome, predispose to cancer and abnormal myelopoiesis in infancy. This review focuses on juvenile myelomonocytic leukemia (JMML), a malignancy of early childhood characterized by initiating germline and/or somatic mutations in five genes of the RAS/MAPK pathway: PTPN11, CBL, NF-1, KRAS and NRAS. Natural courses of these five subtypes differ, although hematopoietic stem cell transplantation remains the only curative therapy option for most children with JMML. With whole-exome sequencing studies revealing few secondary lesions it will be crucial to better understand the RAS/MAPK signaling network with its crosstalks and feed-back loops to carefully design early clinical trials with novel pharmacological agents in this still puzzling leukemia.
authors.affiliation: Department of Pediatric Hematology and Oncology, Universitätsklinikum Freiburg, Germany charlotte.niemeyer@uniklinik-freiburg.de.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
mesh_terms: D002648:Child; D002675:Child, Preschool; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction; D013577:Syndrome; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins