Abstract
Germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK pathway are the hallmarks of a newly classified family of autosomal dominant syndromes termed RASopathies. Myeloproliferative disorders (MPDs), in particular, juvenile myelomonocytic leukemia, can lead to potentially severe complications in children with Noonan syndrome (NS). We studied 27 children with NS or other RASopathies and 35 age-matched children as control subjects. Peripheral blood (PB) cells from these patients were studied for in vitro colony-forming units (CFUs) activity, as well as for intracellular phosphosignaling. Higher spontaneous growth of both burst-forming units-erythroid (BFU-E) and CFU-granulocyte/macrophage (CFU-GM) colonies from RAS-mutated patients were observed as compared with control subjects. We also observed a significantly higher amount of GM-colony-stimulating factor-induced p-ERK in children with RASopathies. Our findings demonstrate for the first time that PB cells isolated from children suffering from NS or other RASopathies without MPD display enhanced BFU-E and CFU-GM colony formation in vitro. The biological significance of these findings clearly awaits further studies. Collectively, our data provide a basis for further investigating of only partially characterized hematological alterations present in children suffering from RASopathies, and may provide new markers for progression toward malignant MPD in these patients.
Highlights
The presence of germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK mitogen-activating protein kinase (MAPK) cascade is the molecular basis for a newly classified family of autosomal dominant syndromes termed ‘RASopathies’
It has been shown that individuals with Noonan syndrome (NS) are at increased risk of developing a myeloproliferative disorder (NS/Myeloproliferative disorders (MPDs)) that may resolve spontaneously or progress to Juvenile myelomonocytic leukemia (JMML).[25,26,27] neuro cardio facial cutaneous syndromes, in particular NS, are related to JMML in terms of both germline and somatic mutations of genes involved in the RAS/MAPK signaling pathway
We demonstrate for the first time that RAS-mutated non-JMML patients are characterized by a significantly higher spontaneous growth rate, in vitro, of both burst-forming units-erythroid (BFU-E)- and colony-forming units (CFUs)-GMcirculating progenitors than control subjects
Summary
The presence of germline mutations in genes coding for molecules involved in the RAS/RAF/MEK/ERK mitogen-activating protein kinase (MAPK) cascade is the molecular basis for a newly classified family of autosomal dominant syndromes termed ‘RASopathies’ These disorders that include Noonan syndrome (NS), LEOPARD syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis 1 and Legius syndrome are developmental syndromes affecting ~ 1 in 1000 live birth.[1,2,3] Each of them exhibits distinctive phenotypic features, there are numerous overlapping clinical manifestations including dysmorphic craniofacial features, congenital cardiac defects, skin, skeletal and ocular abnormalities, varying degrees of intellectual disability and increased cancer risk.[4,5,6] NS, the most common among these disorders, is characterized by heterozygous germline mutation in the PTPN11 gene in approximately half of the cases.[7] The PTPN11 proto-oncogene encodes Src-homology tyrosine phosphatase-2 (SHP-2), a protein tyrosine phosphatase with a role in signal transduction and hematopoiesis.[8]. Analysis of the mutational spectra observed in NS vs JMML patients clearly indicates that germline PTPN11 NS-associated mutations have only a mild effect on development and hematopoiesis when compared with JMML-associated somatic PTPN11 lesions.[15,16,17,18,19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
