title: Peripheral blood cells from children with RASopathies show enhanced spontaneous colonies growth in vitro and hyperactive RAS signaling.
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.
authors.affiliation: M. Tettamanti Research Centre, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaipa
authors.affiliation: M. Tettamanti Research Centre, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bugarin
authors.affiliation: Pediatrics Clinical Genetics, MBBM-AO San Gerardo Foundation, University of Milano-Bicocca, Monza, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cianci
authors.affiliation: M. Tettamanti Research Centre, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Sarno
authors.affiliation: 1] M. Tettamanti Research Centre, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy [2] Center of Pediatric Hematology Oncology, Azienda Policlinico-OVE, University of Catania, Catania, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bonaccorso
authors.affiliation: 1] M. Tettamanti Research Centre, Pediatric Clinic, University of Milano-Bicocca, Monza, Italy [2] Pediatrics Clinical Genetics, MBBM-AO San Gerardo Foundation, University of Milano-Bicocca, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Pediatrics Clinical Genetics, MBBM-AO San Gerardo Foundation, University of Milano-Bicocca, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Selicorni
mesh_terms: D000293:Adolescent; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D007223:Infant; D044542:LEOPARD Syndrome; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008297:Male; D009634:Noonan Syndrome; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018631:ras Proteins